Novel 11-deoxy-substituted prostaglandins of the E and F series

ABSTRACT

This disclosure describes 11-deoxy-11-substituted members of the E2, F2, E1, F1, dihydro E1 and dihydro F1 prostaglandin series which are useful as hypotensive agents and as anti-ulcer agents.

CROSS REFERENCE TO RELATED APPLICATION

This is a continuation of application Ser. No. 552,403 filed Feb. 24,1977, now U.S. Pat. No. 4,057,571, which is a continuation-in-part ofour copending application Ser. No. 274,559, filed July 24, 1972 now U.S.Pat. No. 4,141,914.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel organic compounds of the prostanoic acidclass and their derivatives. In particular, the compounds of thisinvention are 11-deoxy-11-substituted derivatives of this class. Thenovel compounds of this invention embrace all of the optical antipodes,enantiomers, diastereoisomers, racemates, racemic mixtures anddiastereoisomeric mixtures represented by the following generalformulae; of which (A) represents the absolute configuration of themammallian, naturally-occurring prostaglandins. ##STR1## wherein R is amember of the group consisting of alkyl groups of 3 to 7 carbon atoms,alkenyl groups of 3 to 7 carbon atoms, phenyl, and phenoxy-unsubstitutedor substituted with one or two groups selected from the group consistingof lower alkyl, lower alkoxy, nitro, halogen and trifluoromethyl; R₁ isa member of the group consisting of lower alkyl, lower 1-alkenyl,phenyl, lower alkylthio, lower alkanoylthio, sulfhydryl, ω-di(loweralkyl)amino lower alkylthio, cyano, carboxamido, carboxylic acid andalkyl esters thereof, α-nitro lower alkyl, α,α-di(lower carboalkoxy)lower alkyl, α,α-dicarboxy lower alkyl, α-carboxy lower alkyl, di(loweralkyl)sulfonium halide, p-toluenesulfonylate or lower alkylsulfonate,formyl, lower alkanoyl, α,α-di(lower alkoxy)methyl, α,α-ethylenedioxylower alkyl, α-hydroxy-lower alkyl radicals; R₂ is selected from thegroup consisting of hydrogen and an alkyl group having from 1 to 12carbon atoms; R₃ and R₄ are members of the group consisting of hydrogen,fluorine and lower alkyl radicals, not necessarily the same for eachuse; X is a divalent moiety selected from the group consisting of##STR2## wherein R₅ is selected from the group consisting of hydrogen,lower alkanoyl, lower alkylsulfonyl, tetrahydropyranyl and tri(loweralkyl)silyl; R₆ is selected from the group consisting of hydrogen andlower alkyl radicals with the proviso that when R₆ is lower alkyl, thenR₅ is hydrogen; Y is a divalent radical selected from the groupconsisting of: ##STR3## the moiety of -C₅ -C₆ - is ethylene orcis-vinylene; the moiety -C₁₃ -C₁₄ - is ethylene or trans-vinylene; withthe proviso that when -C₅ -C₆ - is cis-vinylene, then -C₁₃ -C₁₄ - mustbe trans-vinylene; with the third proviso that the bonds represented asembrace both possible configurations; and with the further proviso thatthe three substituents at C₈, C₁₂ and C₁₁ of the cyclopentenone ring arenot each cis to each other at the same time.

Suitable lower alkyl and lower alkanoyl groups contemplated by thepresent invention are those having up to four carbon atoms such as, forexample, methyl, ethyl, isopropyl, sec-butyl, formyl, acetyl, propionyl,iso-butryl, etc.

Also embraced within the scope of the present invention are thenon-toxic, pharmaceutically acceptable salts of the novel compounds ofthe present invention when R₂ is hydrogen. The cations comprised inthese salts include, for example, the non-toxic metal cations such asthe sodium ion, potassium ion, calcium ion, and magnesium ion as well asthe organic amine cations such as the tri(lower alkyl)amine cations(e.g., triethylamine), procaine, and the like.

The novel compounds of the present invention are obtainable as yellowoils having characteristic absorption spectra. They are relativelyinsoluble in water but are relatively soluble in common organic solventssuch as ethanol, ethyl acetate, dimethylformamide, and the like. Thecationic salts of the compounds when R₂ is hydrogen are, in general,white to yellow crystalline solids having characteristic melting pointsand absorption spectra. They are relatively soluble in water, methanol,and ethanol but are relatively insoluble in benzene, diethyl ether, andpetroleum ether.

The C₁₁ substituents of the compounds of this invention can beintroduced by a conjugate addition reaction with Δ¹⁰ -9-keto prostenoicacid and their derivatives, commonly referred to as prostaglandins ofthe A series, or by a subsequent transformation of an already presentC₁₁ -substituent.

A substituent at C₁₁ trans to the C₁₂ chain is said to be in the αconfiguration and its bond to C₁₁ is represented by |||||||. Conversely,a substituent at C₁₁ cis to the C₁₂ chain is in the β configuration(also termed 11-epi) and its bond to C₁₁ is represented by a solid line;a bond represented by a indicates that both the 11α and 11βpossibilities are embraced. When the oxy substituent at C₁₅ is in the αor "normal" configuration, the bond is represented by ||||| and when itis in the β or "epi" configuration the bond is indicated by .

Among the reagents which can be utilized for conjugate addition arelithio di(lower alkyl)cuprates (e.g. lithio dimethylcuprate), lithiodi(lower 1-alkenyl)cuprates, lithio diphenyl cuprate, lower alkylmercaptans, ω-di(lower alkyl)amino lower alkyl mercaptans, thio loweralkanoic acids, acetone cyanohydrin (for cyanide introduction),1-nitro-lower alkanes, di(lower alkyl)malonates as well as di(loweralkyl)mono-lower alkyl substituted malonates, lower primary andsecondary alcohols, 1,3-dioxolan and lower 2-alkyl 1,3-dioxolans. Withthe exception of the lithio di(lower alkyl)cuprates and lithio di(loweralkenyl)cuprates, the various reagents generally require catalyticconditions for effective conjugate addition. The appropriate conditionsfor each reagent are apparent from the examples included herein.Illustrative conjugate addition reacts using the naturally occurringl-15-O-acetylprostaglandin-A₂ methyl ester (I) are shown in Flowsheets Athrough G, wherein R₇ is a lower alkyl group, lower 1-alkenyl group, orphenyl, R₈ is a lower alkanoyl group, R₉ is hydrogen or a lower alkylgroup, R₁₀ is a lower alkyl group, and X is halogen,p-toluenesulfonyloxy, or lower alkylsulfonyloxy. ##STR4##

In accordance with Flowsheet A, treatment of 15-O-acetylprostaglandin-A₂methyl ester with a lithio-dialkyl, dialkenyl or diphenylcuprateprovides a mixture of the11-deoxy-11-substituted-15-O-acetylprostaglandin-E₂ methyl ester and the11-deoxy-11-substituted-15-substituted-prostaglandin-E₂ methyl ester.The use of the 15-hydroxy function to prevent the interaction of the15-acetoxy group is described hereinbelow. Also in accordance withFlowsheet A is shown the conjugate addition of α,α-dicarboxylower alkyland α-nitro lower alkyl groups.

The preparation of 11-deoxy-11-loweralkanoylthio-15-O-acetylprostaglandin-E₂ methyl esters by the heating ofI in a thiolcarboxylic acid is illustrated in Flowsheet C. Alsoillustrated is the preparation of the 11-deoxy-11α-loweralkylthio-15-O-acetylprostaglandin-E₂ methyl ester (X) and itssubsequent methanolysis to give XI.

The utility of XI to prepare PGA₂ methyl ester (XIII) is shown inFlowsheet D; (XIII) is not directly obtainable from I by the usualchemical procedures.

The preparation of the free 15-hydroxy derivative (XIII) from (I) isdifficult to achieve directly by the usual acid-or-base-catalyzedconditions of hydrolysis. Under these circumstances (I) is too unstableand elimination to the novel tetraene (XXIII) is observed. ##STR5##

In order to prepare the free 15-hydroxy derivative we have developed aconvenient and novel procedure, which we consider to be a part of thisinvention. This procedure involves the conjugate addition to the diesterof an alkyl/mercaptan (e.g., methyl mercaptan or ethyl mercaptan) togive the 11-alkylthio derivative (X). Saponification of diester (X) withpotassium carbonate in the presence of excess alkyl mercaptan thenprocedes smoothly to provide the free 15-ol 11-alkylthio derivative(XI). The presence of alkyl mercaptan during this treatment presumablymaintains the 11-alkylthio group, which otherwise would be eliminatedunder these conditions to give the Δ¹⁰ -9-keto system, unstable tosaponification conditions. Thus, in effect this procedure protects thislatter system during saponification. The Δ¹⁰ -function can then beregenerated under conditions to which it is stable by enhancing theleaving potential of the alkylthio group by conversion to a sulfoniumsalt (XII) which is eliminated readily with sodium bicarbonate to givethe methyl ester (XIII) of PGA₂. The overall yield for the conversion of(I) to (XIII) is quite high, on the order of 70-85%, and several of thesteps can be combined.

The free 15-ol (XIII) is a useful intermediate. For example, treatmentwith lithium dialkyl cuprates provides high yields of the 11-lower alkylderivatives without involvement of the 15-oxy function. When the samereagent is used to treat the diester (I) the 15-acetoxy function becomesinvolved and a substantial portion of the product is the 11,15-di(loweralkyl) derivative (III).

As illustrated in the Flowsheet E, the treatment of the diester (I) withacetone cyanohydrin affords a mixture of 11α and 11β nitriles.Hydrolysis using saturated aqueous potassium cyanide in methanol yieldsthe two epimeric nitriles (XV) and (XVI), separable by columnchromatography (Example 212).

A unique photensitized addition of lower primary and secondary alcohols,1,3-dioxolan, and 2-substituted 1,3-dioxolans to the enone system ofprostaglandins-A is also disclosed in this invention and is illustratedin Flowsheet G.

The irradiation of a solution of 15-O-acetylprostaglandin-A₂ methylester (I) in an alcohol containing benzophenone using a pyrex filter andmedium pressure lamp provides the11-deoxy-11-substituted-15-O-acetylprostaglandin-E₂ methyl ester (XXI).Likewise irradiation using 1,3-dioxolans as solvent yields11-deoxy-11α-(1,3-dioxolan-2-yl)-15-O-acetylprostaglandin-E₂ methylester derivatives (XX); acid hydrolysis of whic provides thecorresponding 11-formyl or acyl derivatives.

Other novel compounds embraced by this invention can be prepared byfurther transformations of the above-described conjugate additionproducts. Thus, for example, hydrolysis of the malonate addition product(VI) furnishes the 11-(α,α-dicarboxy lower alkyl) derivative (VII),decarboxylation of which provides the 11-(α-carboxy lower alkyl)derivative (VIII). Treatment of the 11-cyano derivative (XIV), withalkaline hydrogen peroxide gives the 11-caboxamido diester (XVII), whichon mild hydrolysis (three equivalents of potassium hydroxide, threehours, ambient temperature) gives the corresponding 15-hydroxycarboxylic acid (XVIII). Vigorous alkaline hydrolysis of (XVIII) thenyields the 11-carboxylic acid derivatives (XIX).

Certain of the other products embraced by this invention can be obtainedby substituting members from the following Table of prostaglandins A forl-15-O-acetylprostaglandin-A₂ methyl ester (I) or the corresponding free15-ol (XIII) of Flowsheets A through G:

                  TABLE I                                                         ______________________________________                                        l-13-dihydroprostaglandin-A.sub.1.sup. a                                      l-prostaglandin-A.sub.1.sup. a                                                l-prostaglandin-A.sub.2.sup. b                                                l-15-epi-O-acetylprostaglandin-A.sub.2 methyl ester.sup. c                    l-15-epi-prostaglandin-A.sub.2.sup. c                                         dl-prostaglandin-A.sub.1.sup. d                                               l-15-methylprostaglandin-A.sub.1 methyl ester.sup. e                          d-15-methylprostaglandin-A.sub.2 methyl ester.sup. e                          l-16,16-dimethylprostaglandin-A.sub.1.sup. f                                  l-16(S)-methylprostagladin-A.sub.2.sup. g                                     l-16(R)-methylprostaglandin-A.sub.2.sup. g                                    l-16(S)-methylprostaglandin-A.sub.1.sup.g                                     l-16(R)-methylprostaglandin-A.sub.1.sup. g                                    l-16,16-difluoroprostaglandin-A.sub.2.sup. h                                  l-16-fluoroprostaglandin-A.sub.2.sup. h                                       l-20-methylprostaglandin-A.sub.2 (Example 108)                                l-20-ethylprostaglandin-A.sub.2 (Example 103)                                 d,1-17,20-tetranor-16-p-fluorophenoxyprostaglandin-A.sub.2                    (Example 113)                                                                 l-17,20-tetranor-16-p-fluorophenoxyprostaglandin-A.sub.2                      (Example 106)                                                                 d,1-17,20-tetranor-16-m-chlorophenoxyprostaglandin-A.sub.2                    (Example 111)                                                                 l-17,20-tetranor-16-m-chlorophenoxyprostaglandin-A.sub.2                      (Example 104)                                                                 d,1-17,20-tetranor-16-m-trifluoromethylphenoxyprostaglandin-A.sub.2           (Example 114)                                                                 l-17,20-tetranor-16-m-trifluoromethylphenoxyprostaglandin-A.sub.2             (Example 107)                                                                 l-17,20-tetranor-16-phenoxyprostaglandin-A.sub.2 (Example 105)                d,1-17,20-tetranor-16-phenoxyprostaglandin-A.sub.2 (Example                   ______________________________________                                        112)                                                                           REFERENCES                                                                    .sup.a F.H. Lincoln et al., Journ. Org. Chem., 38, 956 (1973).                .sup.b W.P. Schneider, R.D. Hamilton, L.E. Rhuland, Journ. Amer. Chem.        Soc., 94 2122 (1972).                                                         .sup.c R.L. Spraggins and A. Weinheimer, Tetrahedron Letters, 5185,           (1969).                                                                       .sup.d E.J. Corey et al., Journ. Amer. Chem. Soc., 90, 2246 (1968).           .sup.e G.L. Bundy et al., Advances in the Biosciences, 9, International       Conference on Prostaglandins, 128 (1972).                                     .sup.f Belgium Patent No. 782,822.                                            .sup.g M. Hayashi et al., Journ. Org. Chem., 38 1250 (1973).                  .sup.h Netherlands Patent No. 7,305,817.                                 

The configuration of the various substituents introduced at C-11 hasbeen established for nearly all of the compounds disclosed herein.

In the case of the 11-alkylthio derivatives, a single isomer (11α)almost totally predominates although traces of the 11β epimer aredetected. In the 11-alkyl and 11-alkenyl series the available evidenceindicates that a single isomer predominates. The evidence andtheoretical considerations leads to the assignment to these epimers ofthe 11-normal configuration, i.e., a trans-relationship between the11-substituent and the adjacent side chain.

The introduction of the 11-cyano moiety appears to yield mearly equalamounts of both the 11α and 11β epimers. This epimeric mixture isobtained when one uses either a diester such asl-15-O-acetylprostaglandin-A₂ methyl ester or a free hydroxy acid suchas l-PGA₂. These epimers are separable from each other bychromatographic procedures.

The stereochemistry of the 11-hydroxy-lower alkyl derivatives isdependent upon the alcoholic reagent utilized. Methanol leads to aseparable epimeric mixture of 11α-hydroxymethyl and 11β-hydroxymethylepimers in about a 1:3 ratio, respectively. With isopropanol the productis largely the 11α-(1-hydroxy-1-methylethyl) derivative.

The photeosensitized introduction of 1,3-dioxolan yields a separablemixture of 11α and 11β-(1,3-dioxolan-2-yl) derivatives in a 1:3 ratio.

The 11α-substituted products of this invention can be epimerized to amixture containing the 8-normal and 8-iso epimers. This is illustratedin Flowsheet H using 11-deoxy-11α-hydroxymethylprostaglandin-E₂ as anexample. ##STR6##

Esterification of the free 15-hydroxy function as well as of the freecarboxylic acid function by the usual procedures provides the otherester derivatives of this invention.

The products of this invention that have the 15-oxy function in the (S)or "normal" configuration can be converted to the alternate (R) or "epi"configuration by two procedures, illustrated below in Flowsheet I forthe 11-methyl series.

Treatment of (XXV) with a solution of sodium formate in formic acidinduces racemization of the 15-oxy function and a mixture of the 15(R)and 15(S) formyloxy derivatives (XXIII) and (XXIV) are obtained.Separation of this mixture by chromatography provides the individualcomponents and formate hydrolysis gives the original 15(S)-ol (XXV) andthe inverted 15(R)-ol (XXVIII).

Epimerization of the 15(S)-ol (XXV) can be accomplished by conversion toa sulfonyloxy derivative (XXVI), such as methanesulfonyloxy, bytreatment with methanesulfonic acid anhydride at low temperatures in thepresence of an organic base such as triethylamine. The sulfonyloxyderivative (XXVI) is then treated with tetraethyl ammonium formate in asuitable organic solvent to produce the inverted 15(R)-formyloxyderivative (XXIV). Formate hydrolysis then provides the 15(R)-alcohol(XXVIII).

Likewise, compounds of this invention that contain the 15(R)-hydroxyfunction can be epimerized to either the 15(S) or a mixture of 15(S) and15(R) derivatives. ##STR7##

The 9-oxo derivatives (E-series) of this invention can be converted tothe corresponding 9-hydroxy derivatives (F-series) by either anon-selective carbonyl reduction with a reagent such as sodiumborohydride in an alcohol solvent, or stereoselectively with a reagentsuch as lithium-9b-boraphenalyl hydride (XXIX) [H. C. Brown and W. C.Dickason, Journ. Amer. Chem. Soc. 92, 709 (1970)] or lithiumtri-sec-butylborohydride (XXX) in an ether solvent [H. C. Brown and S.Krishnamurthy, Journ. Amer. Chem. Soc., 94, 7159 (1972)]. ##STR8## Inaccordance with Flowsheet J, treatment of the 9-keto derivative (XXXI)in a solvent such as ethanol with sodium borohydride will provide amixture of the corresponding 9α and 9β hydroxy products which can beseparated into their individual components by the usual chromatographictechniques. Stereoselectivity in this reduction can be realized by usinga bulky reagent such as (XXIX) or (XXX) in a solvent such astetrahydrofuran to provide, after borane hydrolysis, predominately, thecis-hydroxy (9α) species (XXXII) when the 11-substituent is in theα-configuration. In the particular case of compounds containing the8-iso configuration (the two side chains being cis to each other) sodiumborohydride again yields a mixture of 9α and 9β hydroxy compounds.However, the use of the bulky stereoselective reagents (XXIX) and (XXX)will yield predominantly the 9β hydroxyl, that is, the hydroxyl at the 9position is cis to the carboxylic acid side chain.

These reductions are illustrated in Flowsheet K. ##STR9##

The novel compounds of this invention which are members of theprostaglandin E₂ and F₂ series can be converted to other novelderivatives of the 11-deoxy prostaglandin E₁ and F₁ series bypreferential reduction of the Δ⁵ cis-double bond. This can be achievedby careful catalytic hydrogenation in the presence of a metal catalystsuch as palladium-carbon or RhCl [P(C₆ H₅)₃ ]₃ or by use of diimide.Selectivity for the reduction of the Δ⁵ bond can be enhanced by firstconverting the 15-ol to a derivative which sterically hinders theapproach to the competing Δ¹³ double bond. Useful 15-hydroxy derivativesfor this purpose include the tetrahydropyranyl derivative and thedimethylisopropylsilyl ether.

This invention also includes the novel 11-substituted derivatives of13-dihydro-11-deoxy-prostaglandin E₁ and F₁. These compounds, in whichall of the double bonds are saturated, can be prepared by catalytichydrogenation in the usual manner of the corresponding members of theE₃, F₃, E₂, F₂, E₁, or F₁ series. (F derivative of the 1 or dihydro-1series can be prepared from the corresponding F₂ derivative by partialor full hydrogenation as just described or by reduction of the9-carbonyl function of the corresponding E compound).

The compounds of this invention are useful as protective agents againstthe ulcerogenic and gastrointestinal effects induced by certainotherwise valuable pharmaceutical agents, particularly non-steroidalanti-inflammatory agents such as indomethacin, phenylbutazone, andaspirin. Indicative of the serious nature of this problem are thefollowing statements concerning indomethacin (Indocin®) taken fromPhysician's Desk Reference 1972 (Medical Economics Inc., Oradell, NewJersey), p. 964.

"Gastrointestinal Effects:

Because of the occurrence and, at times, severity of gastrointestinalreactions to INDOCIN, the prescribing physician must be continuouslyalert for any sign of symptom signalling a possible gastrointestinalreaction. The risks of continuing INDOCIN therapy in the face of suchsymptoms must be weighed against the possible benefits to the individualpatient. The gastrointestinal effects may be reduced by giving the drugimmediately after meals, with food, or with antacids. As advancing yearsappear to increase the possibility of adverse reactions, INDOCIN shouldbe used with concomitantly greater care in the aging."

"Gastroinestinal Reactions:

Single or multiple ulcerations, including perforation and hemorrhage ofthe esophagus, stomach, duodenum or small intestines. Fatalities havebeen reported to occur in some instances. Gastrointestinal bleedingwithout obvious ulcer formation. Perforation of pre-existing sigmoidlesions (diverticulm, carcinoma, etc.). Increased abdominal pain inulcerative colitis patients or the development of ulcerative colitis andregional ileitis have been reported to occur rarely. Gastritis maypersist after the cessation of the drug. Nausea, vomiting, anorexia,epigastric distress, abdominal pain and diarrhea."

It is further to be noted that although prostaglandins in general arenot effective when administered by oral route, the compounds of thisinvention are effective orally. The assay to determine the protectiveeffect of these compounds is carried out in the following manner.

Rats were starved for 48 hours (water was given ad libitum).Indomethacin (20 mg./kg. of body weight) was administered by thesubcutaneous route and one-half the dose of the test compound wasadministered by gavage at the same time. After three hours, the secondhalf of the test compound was administered, also by gavage. Five hoursafter the administration of indomethacin the animals were decapitatedand the stomachs removed. The stomachs were washed with distilled water,blotted on gauze, cut along the larger curvature, and the contentsrinsed with distilled water. The stomachs were spread out, pinned on acork and visualized under magnifying glass for ulcers. The criteria forscoring of ulcers was as previously reported. [Abdel-Galil et al. Brit.J. Pharmac. Chemotherapy 33:1-14 (1968)].

    ______________________________________                                        Score                                                                         ______________________________________                                        0          Normal Stomach                                                     1          Petechial hemorrhage of pin point ulcers                           2          1 or 2 small ulcers                                                3          Many ulcers, a few large                                           4          Many ulcers, mainly large                                          ______________________________________                                    

Control animals treated with indomethacin but not test compoundconsistenly give scores of about 2.5-3.5. Control animals treated withneither indomethacin not test compound give scores of about 0.5-0.8. Theresults obtained in this assay with typical compounds of the presentinvention are set forth in the table below. Compounds diminishing thecontrol ulcer score by 0.5 unit or more are considered to be active.

                  TABLE I                                                         ______________________________________                                                                SCORE                                                                     Total oral                                                                              Treat-                                                              dose;     ed                                                                  mg./kg. of                                                                              Ani-    Con-                                    Compound            body weight                                                                             mals    trols                                   ______________________________________                                        l-11α/β-cyano-11-deoxyprosta-                                      glandin-E.sub.2 -methyl ester                                                                     25        1.3     2.7                                     l-11α/β-cyano-11-deoxyprosta-                                      glandin-E.sub.2     12.5      1.2     2.5                                     l-11α-nitromethyl-11-deoxyprosta-                                       glandin-E.sub.2     100       1.0     3.2                                     l-11α-methylthio-11-deoxyprosta-                                        glandin-E.sub.2 15-O-acetate methyl                                           ester               50        2.0     2.7                                     l-11α-methyl-11-deoxyprostaglandin-                                                         6.25      2.5     3.0                                     E.sub.2             12.5      2.0     3.0                                                         25.0      1.7     3.0                                     l 11α-carboxamido-11-deoxyprosta-                                       glandin-F.sub.2 α                                                                           50        2.3     3.2                                     l-11α-β-cyano-11-deoxyprosta-                                                          50        1.3     3.0                                     glandin-E.sub.2 15-O-acetate methyl ester                                                         12.5      2.0     2.7                                     l-11α-methyl-11-deoxy-13-dihydro-                                                           50        1.7     3.0                                     prostaglandin-E.sub.1                                                                             12.5      2.3     3.0                                     l-11α-methyl-11-deoxyprostaglandin-                                     F.sub.2 α     25        1.8     2.7                                     l-11α,15-dimethyl-11,15-bisdeoxy-                                       prostaglandin-E.sub.2 α                                                                     50        2.2     3.0                                     l-11α-cyano-11-deoxyprostaglandin-                                      F.sub.2 α     25        1.3     2.8                                     l-11α-ethyl-11-deoxyprostaglandin-                                      E.sub.2             25        2.2     3.0                                     l-11α-ethyl-11-deoxyprostaglandin-                                      F.sub.2 α     25        2.2     3.0                                     l-11α-phenyl-11-deoxyprostaglandin-                                     F.sub.2 α     25        2.0     3.9                                     l-11α-nitromethyl-11-deoxyprosta-                                       glandin-F.sub.2 α                                                                           50        1.8     2.5                                     l-11α-methylthio-11-deoxyprosta-                                        glandin-F.sub.2 α                                                                           12.5      1.2     2.7                                     ______________________________________                                    

The novel compounds of the present invention are effective inhibitors ofgastric acid secretion and of ulcer development in experimental animals,and thus are potentially valuable as agents for the control of gastricsecretion and of gastric erosion and as anti-ulcer agents. Gastric acidsecretion inhibotory action is usually measured by the "Shay rat"procedure .sup.(1,2) with some modifications as follows.

The rats (male, CFE strain) were starved for 48 hours (water was givenad libitum) to permit evacuation of stomach contents. On the morning ofthe experiment, under ether anesthesia, the abdominal region was shavedand a midline incision (1-1/2") was made with a scapel. With the help ofa closed curved hemostat the duodenum was picked up. Upon getting theduodenum into view, fingers were used to pull the stomach through theopening, the stomach was then gently manipulated with fingers to ridstomach of air and residual matter which were pushed through thepylorus. Two-5 inch sutures were drawn under the pyloric-duodenalpuncture. A ligature, at the juncture, was formed with one of thethreads. The second ligature was also formed but not tightened.

The test compound or the vehicle, usually 1 ml./100 g. body weight, wereinjected into the duodenum as close as possible to the first ligature.After injection the second ligature was tightened below the injectionsite to minimize leakage. The stomach was placed back through theopening into the abdominal cavity, the area of incision was washed withsaline and the incision was closed with autoclips. (Occasionally,instead of an intraduodenal injection, animals were dosed by the oral orsubcutaneous route. In the latter case, dosing was done thirty to sixtyminutes before the operation.)

Three hours later, the rats were decapitated and exanguinated, takingcare that blood did not drain into the esohagus. The abdominal cavitywas exposed by cutting with scissors and the esophagus close to thestomach was clamped off with a hemostat, the stomach was removed bycutting above the hemostat (the esophagus was cut) and between the twosutures. Extraneous tissue was removed, the stomach washed with salineand blotted on gauze. A slit was carefully made in the stomach which washeld over a funnel and the contents were collected in a centrifuge tube.The stomach was further cut along the outside edge and turned insideout. Two ml. H₂ O were used to wash the stomach contents into therespective centrifuge tube. The combined stomach contents and wash werethen centrifuged out for 10 minutes in the International Size 2Centrifuge (setting at 30). The supernatant was collected, volumemeasured and recorded, 2 drops of a phenylphthalein indicator (1% in 95%ethanol) were added and the solution was titrated with 0.02 N NaOH (orwith 0.04 N NaOH when large volumes of stomach contents wereencountered) to pH 8.4 (because of usual coloring of the stomachcontents, phenolphthalein was only used to permit visual indication thatthe end point was near) and the amount of acid present was calculated.

Compounds inducing inhibition of gastric acid secretion of 20% or morewere considered active. In a representative operation, and merely by wayof illustration, the results obtained with this assay with typicalcompounds of the present invention are given in Table II below.

                  TABLE II                                                        ______________________________________                                                        Intraduodenal                                                                 dose, mg./kg. Percent                                         Compound        of body weight                                                                              Inhibition                                      ______________________________________                                        l-11α/β-cyano-11-deoxy-                                            prostaglandin-E.sub.2 15-                                                     O-acetyl methyl                                                               ester           25            51                                              l-11α/β-cyano-11-deoxy-                                            prostaglandin-E.sub.2                                                         methyl ester    50            33                                              l-11α /β-cyano-11-deoxy-                                                           50            79                                              prostaglandin-E.sub.2                                                                         25            31                                              l-11α-cyano-11-deoxy-                                                   prostaglandin-F.sub.2 α                                                                 50            43                                              l-11α-ethylthio-11-                                                     deoxyprostaglandin-                                                           E.sub.2 15-O-acetyl                                                           methyl ester    50            27                                              l-11α-methylthio-11-                                                    deoxyprostglandin-                                                            E.sub.2 15-O-acetyl                                                           methyl ester    50            35                                              l-11α-methyl-11-deoxy-                                                  prostaglandin-E.sub.2                                                                         50            63                                              l-11α-methyl-11-deoxy-                                                  prostaglandin-F.sub.2 α                                                                 50            70                                              l-11α-methyl-11-deoxy-                                                  13-dihydroprosta-                                                             glandin-E.sub.1 50            45                                              l-11α-methyl-11-deoxy-                                                  prostaglandin-E.sub.2                                                         15-O-acetyl methyl                                                            ester           50            63                                              l-11α,15-dimethyl-11,                                                   15-bisdeoxyprosta-                                                            glandin-E.sub.2 methyl                                                        ester           50            40                                              l-11α,15-dimethyl-11,                                                   15-bisdeoxyprosta-                                                            glandin-E.sub.2 50            60                                              l-11-carboxamido-11-                                                          deoxyprostaglandin-                                                           E.sub.2         50            27                                              l-11-carboxamido-11-                                                          deoxyprostaglandin-                                                           F.sub.2 α 50            27                                              l-11α-nitromethyl-11-                                                   deoxyprostaglandin-                                                           E.sub.2         100           74                                              l-11α-vinyl-11-deoxy-                                                   prostaglandin-E.sub.2                                                                         50            59                                              l-11α-methylthio-11-                                                    deoxyprostaglandin-                                                           E.sub.2 methyl ester                                                                          100           55                                              l-11α-isopropyl-11-                                                     deoxyprostaglandin-                                                           E.sub.2         50            42                                              l-11α-phenyl-11-deo                                                     deoxyprostaglandin-                                                           E.sub.2         50            58                                              l-11α-(1-hydroxy-1-                                                     methylethyl)-11-                                                              deoxyprostaglandin-E.sub.2                                                                     8*           31                                              l-11α-hydroxymethyl-                                                    11-deoxyprosta-                                                               glandin-E.sub.2  8*           44                                              l-11α-nitromethyl-11-                                                   deoxyprostaglandin-                                                           F.sub.2 α 50            38                                              l-11α-methylthio-11-                                                    deoxyprostaglandin-                                                           F.sub.2 α 50            61                                              ______________________________________                                         *subcutaneous route of administration                                    

Inhibition of basal gastric acid secretion can be determined by thefollowing procedure.

Female Sprague-Dawley rats weighing 140-160 grams are fasted inindividual cages for 18-24 hours. The rats are then lightly anesthetizedwith ether and their front teeth extracted to avoid destruction of theplastic cannula. A midline incision is then made and the stomach andduodenum exposed. A flanged polyvinyl tube is inserted into the fundicportion of the stomach and secured with a purse string suture line using4-O Mersilene. The rat is then dosed by injection of the compound intothe duodenum (1.0 ml. per 100 gram body weight). After dosing, theabdominal wall and skin are closed using metal wound clips. The rat isreplaced in a cage containing a longitudinal slit to allow the polyvinyltube to hang freely. An 8 ml. plastic collecting tube is attached to theflanged cannula and hangs freely below the cage. The first 30 minutesample is discarded designating this time as zero. The collecting tubeis attached again and samples removed at the end of 60 and 120 minutes.These samples are referred to as "A" and "B" in the table. The hourlysamples are then transferred to a 15 ml. centrifuge and centrifuged for5-10 minutes. Total and sediment volume are then recorded with thesupernatent volume being used as volume of secretion. A 1 ml. or lessaliquot is then removed and placed in a 50 ml. beaker containing 10 ml.of distilled water. This sample is then titrated using 0.01 N NaPH to pH7.0 using a Beckman zeromatic pH meter. Volume, titratable acidity(mew/L) and total acid output (ueq/hour) are recorded. Percentinhibition is determined by comparison with the appropriate control.Groups of three rats were used for preliminary testing, and groups ofsix rats were used for dose-response evaluations. All compounds areadministered in a vehicle consisting of 0.5% methocel, 0.4% tween 80,and saline at a constant volume of 1 ml./100 gram rat. Samples aredispersed by sonification. Percent inhibition is calculated on basis ofconcurrent vehicle control.

In Table III which follows is given the effect on total acid outputafter 60 minutes and 120 minutes of intraduodenal dose, ofrepresentative compounds of this invention.

                                      TABLE III                                   __________________________________________________________________________    Inhibition of Total Acid Output in the Acute Gastric Fistula Rat                                          % Inhibition of Total Acid                                                    Output                                                                Dose mg./kg.                                                                          After 60                                                                            After 120                                   Compound            of body weight                                                                        minutes (A)                                                                         minutes (B)                                 __________________________________________________________________________    l-11-acetylthio-11-deoxyprostaglandin-E.sub. 2                                                    10      66    68                                          l-11α-ethylthio-15-O-acetyl-11-deoxy-                                                       10      80    24                                          prostaglandin-E.sub.2 methyl ester                                                                5       19    59                                                              2.5     54    51                                          l-11α-ethyl-11-deoxyprostaglandin-E.sub.2                                                   10      57    66                                          l-11β-cyano-11-deoxyprostaglandin-E.sub.2                                                    10      26    43                                          l-11α-cyano-11-deoxyprostaglandin-E.sub.2                                                   10      49    18                                          l-11-cyano-16-O-acetyl-11-deoxy-                                              prostaglandin-E.sub.2 methyl ester                                                                10      40    34                                          l-11-carboxamido-11-deoxyprostaglandin-                                       E.sub.2             10      27    35                                          l-11-mercapto-11-deoxyprostaglandin-F.sub.2 α                                               10      44    55                                          l-11β-hydroxymethyl-11-deoxyprosta-                                      glandin-F.sub.2 α                                                                           10       0    43                                          l-11α-(1-hydroxy-1-methylethyl)-11-deoxy-                               prostaglandin-F.sub.2 α                                                                     10      36    35                                          l-11α-vinyl-11-deoxyprostaglandin-F.sub.2 α                                           5       53    67                                                              2.5     15    37                                          l-11α-isopropyl-11-deoxyprostaglandin-                                  F.sub.2 α     10      44    35                                          l-9α-hydroxy-11α,15-dimethyl-5-cis,                               13-trans-prostadienoic acid                                                                       10      25    20                                          l-11α-hydroxymethyl-11-deoxyprosta-                                     glandin-F.sub.2 β                                                                            5       49    49                                          l-11α-hydroxymethyl-15-O-acetyl-11-                                     hydroxyprostaglandin-F.sub.2 β methyl ester                                                  5       47    33                                          __________________________________________________________________________

An important consideration in the use of prostaglandin like substancesfor the inhibition of gastric acid secretion and the treatment ofulcers, etc. is that they do not at the same time induce diarrhea, acommon phenomenon observed on administration of the prostaglandins. Itis therefore unexpected and novel that in general, the compounds of thisinvention are not diarrheagenic at dose levels at which they areeffective gastric acid secretion inhibitors. One measure ofdiarrheagenic potential is the ileal ligated rat assay, a description ofwhich follows directly.

Female Sprague-Dawley rats (Charles River Laboratories) weighing lessthan 100 grams are fasted in individual cages for at least 18 hours.They are then anesthetized with ether and a midline incision made. Theduodenum is exposed and the test drug or control injectedintraduodenally. The ileocecal junction is then exposed and the terminalileum is ligated using 3-0 silk thread just proximal to the junction.The incision is then closed using wound clips. Rats are placed back inindividual cages without food or water for four hours. After this timethe rats were sacrificed, the stomach and small intestine carefullyremoved, and cleaned of adherent mesentery. The removed portion of gutis then weighed to the nearest 0.1 gram. Compounds inducing diarrheasuch as prostaglandins, cholera toxin, etc. produce an increase inweight of the ligated intestine. This increase from control is noted inTable IV, as change in weight in grams after standardizing weights ofgut to grams/100 gram rat. An increase in intestinal weight of about 1.0g. is considered indicative of diarrheagenic potential.

When measured by this assay at effective gastric acid secretioninhibiting doses, as determined by the acute rat fistula assayrepresentative novel compounds of Table IV are non-diarrheagenic.

                  TABLE IV                                                        ______________________________________                                        Ideal-Ligated Rat Assay                                                                                     Increase                                                        Intraduodenal in weight                                                       dose, mg./kg. of intes-                                       Compound        of body weight                                                                              tine, g.                                        ______________________________________                                        l-11-acetylthio-11-                                                                           20            -0.1                                            deoxyprostaglandin-E.sub.2                                                                    10            -0.02                                           l-11α-ethylthio-11-                                                     deoxyprostaglandin-E.sub.2                                                                    10            -0.2                                            l-11α-vinyl-11-deoxy-                                                   prostaglandin-F.sub.2 α                                                                 10            -0.36                                           l-11α-hydroxymethyl-                                                    11-deoxyprostaglandin-                                                        F.sub.2 β  10            +0.6                                            l-11α-hydroxymethyl-                                                    15-O-acetyl-11-deoxy-                                                         prostaglandin-F.sub.2 β                                                  methyl ester    10            +0.15                                           ______________________________________                                    

The E-type prostaglandin of this invention show bronchodilator activityin experimental animals and are potentially useful in the treatment ofbronchial asthma.

Bronchodilator activity was determined in guinea pigs againstbronchospasms elicited by intravenous injections of 5-hydroxytryptamine,histamine or acetylchlorine by the Konzett procedure. [See J. Lulling,P. Lievens, F. El Sayed and J. Prignot, Arzneimittel-Forschung, 18, 995(1968).]

In the Table which follows bronchodilator activity for representativecompounds of this invention against one or more of the three spasmogenicagents is expressed as an ED₅₀ determined from the results obtained withthree logarithmic cumulative intravenous doses.

                                      TABLE V                                     __________________________________________________________________________    Bronchodilator Activity (Konzett Assays)                                      ED.sub.50, mg./kg.                                                                                Spasmogenic Agent                                                             5-hydroxy-   acetyl-                                      Compound            tryptamine                                                                           histamine                                                                           choline                                      __________________________________________________________________________    l-11α-methyl-11-deoxy-13-dihydro-                                       prostaglandin-E.sub.1            0.773                                        l-11α-cyano-11-deoxyprostaglandin-F.sub.2 α                                                  1.66                                               l-11-α-methyl-11-deoxyprostaglandin-F.sub.2 α                                         0.038  0.013                                              l-11α-methyl-11-deoxyprostaglandin-E.sub.2                                                  0.0022 0.050 1.19                                         l-11α,15-dimethyl-11,15-bis-deoxy-                                      prostaglandin-E.sub.2                                                                             18.1                                                      l-11α/β-cyano-11-deoxy-prostaglandin-E.sub.2                                           .0036  0.0054                                                                              0.091                                        l-11α-vinyl-11-deoxyprostaglandin-E.sub.2                                                   1.20   1.30                                               l-11α-isopropyl-11-deoxyprosta-                                         glandin-E.sub.2     8.95                                                      l-11α-phenyl-11-deoxyprostaglandin-E.sub.2                                                  .46                                                       l-11α-carboxamido-11-deoxyprosta-                                       glandin-E.sub.2     1.7    0.53                                               l-11α-carboxymethyl-11-deoxyprosta-                                     glandin-E.sub.2     5.5    3.4   4.6                                          l-11α-dicarboxymethyl-11-deoxy-                                         prostaglandin-E.sub.2                                                                             3.3                                                       l-11α-nitromethyl-11-deoxyprosta-                                       glandin-E.sub.2            1.4   1.7                                          l-11α-cyano-11-deoxyprostaglandin-F.sub.2 α                                           0.03   0.019 0.015                                        l-11α-methylthio-11-deoxyprosta-                                        glandin-F.sub.2 α                                                                           2.63   1.6                                                l-11α-ethyl-11-deoxyprostaglandin-E.sub.2                                                          1.24  3.9                                          l-11β-hydroxymethyl-11-deoxyprosta-                                      glandin-E.sub.2     0.30   0.065 0.25                                         l-11β-cyano-11-deoxyprostaglandin-E.sub.2                                                    3.1    54.9                                               l-11α-cyano-11-deoxyprostaglandin-E.sub.2                                                   0.30 × 10.sup.-3                                                               1.4 × 10.sup.-3                                                               5.3 × 10.sup.-3                        __________________________________________________________________________

The novel compounds of the present invention also have potential utilityas hypotensive agents, abortifacients, agents for the induction oflabor, agents for the induction of menses, fertility-controlling agents,central nervous system regulatory agents, salt and water-retentionregulatory agents, diuretics, and as inhibitors of platelet aggregation.Certain of the novel compounds of this invention possess utility asintermediates for the preparation of other of the novel compounds ofthis invention.

This invention will be described in greater detail in conjunction withthe following specific examples.

EXAMPLE 1 Isolation of the methyl ester of 15-O-acetylprostaglandin A₂from Plexaura Homomalla (esper)

Specimens of Plexaura Homomalla (esper) are collected in Puerto Ricanwaters, air dried and stored under a nitrogen atmosphere at 0° C. Thecortex is removed, ground and extracted with isomeric hexanes. Theorganic solvent is evaporated in vacuo to afford a prostaglandincontaining residue. The residue is dissolved in nitromethane andextracted with isomeric hexanes. The nitromethane solution is evaporatedto give a residue that is approximately 50% by weight of the residueprior to the nitromethane treatment. This process, in addition to theremoval of unwanted materials, (largely fatty esters), also has thebenefit of selectively removing the sterols that have nearly the same rfindex on silica gel as that of the methyl ester of15-O-acetylprostaglandin A₂.

Purification of the residue via dry column chromatography using acidwashed silica gel and 5% ethyl acetate as elutant yields the15-O-acetyl-prostaglandin A₂ methyl ester and prostaglandin A₂ methylester. The combined yield of the two prostaglandins is 1-2%.

The configuration of the C-15 carbon is established by degradation withozone followed by chromic acid oxidation to yield α-acetoxyheptanoicacid. The configuration of the acetoxy grouping is established bycomparison of the circular dichromism curves of α-acetoxyheptanoic acidand D-α-acetoxypropanoic acid prepared from the calcium salt of D-lacticacid (R-configuration). Compounds of like configuration will displaycurves of the same sign. D-α-acetoxypropanoic acid displays a negativecircular dichromism curve whereas the degradation product,α-acetoxyheptanoic acid gives a positive circular dichromism curve.

EXAMPLE 2 Preparation of 11-deoxy-11α-ethylthio-15-O-acetylprostaglandin E₂ methyl ester--Method A

To a solution of 7.23 gm. of the methyl ester of15-O-acetyl-prostaglandin A₂ in a mixture of 15 ml. ethanethiol, 15 ml.of tetrahydrofuran and 15 ml. of methanol is added 1.8 ml. of aqueous 5%sodium bicarbonate. The solution is stirred for twenty minutes and isevaporated in vacuo at 30° C. to a paste. To the paste is added 25 ml.ether and 10 ml. of water. The ether is separated and washed with brine.The aqueous layer is extracted with ether and the ether is washed withbrine and the ether extracts are combined, dried with magnesium sulfate,and evaporated in vacuo to afford 8.375 gm. of11-deoxy-11α-ethylthio-prostaglandin E₂ methyl ester as an oil; λmax:1740 cm⁻¹ (saturated ketone and esters), 1225 cm⁻¹ (acetate); [α]_(D) ²⁵=-59.67° (C=0.481 chloroform).

EXAMPLE 3 Preparation of 11-deoxy-11α-methylthioprostaglandin E₂--Method B

A solution of prostaglandin A₂ is treated as in Example 2 except thatone equivalent of sodium bicarbonate in water is added before theaddition of a catalytical amount of 5% aqueous sodium bicarbonate. Inaddition, the solution is acidified with a sodium biphosphate bufferprior to the extraction with ether to yield11-deoxy-11α-methylthioprostaglandin E₂ after evaporation in vacuo ofthe organic solvents.

EXAMPLE 4 Conversion of 15-O-acetylprostaglandin A₂ methyl ester toprostaglandin A₂ methyl ester

To a 0° C. solution containing 12.15 gm. of 15-O-acetylprostaglandin A₂methyl ester in 50 ml. of methanethiol and 100 ml. of methanol is addeda small amount of potassium carbonate. The solution is stirred 30minutes and 75 ml. of methanol and 8.55 gm. of potassium carbonate isadded. The flask is tightly stoppered, secured with rubber bands andstirred at room temperature for two weeks. The solution is cooled to anice bath and poured into 350 ml. of ether and 500 ml. of ice water. Theaqueous layer is extracted with ether and the combined ether extractsare washed with brine and dried with magnesium sulfate. The ether isevaporated in vacuo and the residue is dissolved in 100 ml. of methanoland filtered through celite to remove stop-cock crease. The methanol isevaporated in vacuo to afford 11.67 gm. of crude11-deoxy-11α-methylthioprostaglandin A₂ methyl ester as an oil.

To a solution of 11.67 gm. of crude 11-deoxy-11α-methylthioprostaglandinA₂ methyl ester in a solution of 60 ml. tetrahydrofuran, 30 ml. ofmethanol and 25 ml. of iodomethane is added 70 ml. of a 5% aqueoussodium bicarbonate solution. The resulting solution is stirredvigorously and heated under reflux for four hours to form11-deoxy-11α-dimethylsulfonium iodide prostaglandin A₂ methyl esterwhich is decomposed in solution to afford prostaglandin A₂ methyl ester.

The solution is cooled and added to 200 ml. of ether and 100 ml. ofwater. The aqueous layer is extracted with ether and the ether extractedare combined, washed with brine, dried with magnesium sulfate andevaporated in vacuo to afford 10.63 gm. of the crude prostaglandin A₂methyl ester as an oil.

The oil is purified by dry column chromatography using acid washedsilica gel. The material in methylenechloride is placed onto a 62"×3"flat diameter nylon tube containing the acid washed silica. The columnis developed with ether and is then cut up into 10 equal sections.Sections 6, 7 and 8 are combined and the product is eluted from thesilica gel with 20% methanol in chloroform.

Evaporation in vacuo of the solvents affords 8.64 gm. (80%) ofprostaglandin A₂ methyl ester; λmax 1735 cm⁻¹, 1710 cm⁻¹, 1660 cm⁻¹,3400 cm⁻¹ ; [α]_(D) ²⁵ =+137.5 (C=0.4, chloroform).

Elution of the material from sections 9 and 10 of the column in likefashion yields 1.2 gm. of the starting 15-O-acetyl prostaglandin methylester.

Substitution of ethanethiol for methanethiol in the above procedureresults in the formation of 11-deoxy-11α-ethylthioprostaglandin A₂methyl ester and 11-deoxy-11α-(ethyl methyl sulfonium iodide)prostaglandin A₂ methyl ester as intermediates in the preparation ofprostaglandin A₂ methyl ester.

EXAMPLES 5-12

Treatment of the following A type prostaglandins with the followingalkyl mercaptans in the manner of Example 2 (Method A) or Example 3(Method B) is productive of the 11α-alkylthioprostaglandins (E type) ofthe table.

    __________________________________________________________________________    Example                                                                            Starting Prostaglandin                                                                     Alkyl Mercaptan                                                                        Method                                                                             Product 11α-alkylthio-prostaglandin                                     E                                             __________________________________________________________________________    5    15-O-acetyl prostaglandin                                                                  ethanethiol                                                                            A    11-deoxy-11α-ethylthioprostaglandin                                     E.sub.2                                            A.sub.2 methyl ester       methyl ester                                  6    prostaglandin A.sub.2                                                                      methanethiol                                                                           B    11-deoxy-11α-methylthioprostaglandin                                     E.sub.2                                      7    prostaglandin A.sub.2                                                                      ethanethiol                                                                            B    11-deoxy-11α-ethylthioprostaglandin                                     E.sub.2                                       8    prostaglandin A.sub.2                                                                      1-propanethiol                                                                         B    11-deoxy-11α-isopropylthioprostaglan                                    din                                                                           E.sub.2                                       9    prostaglandin A.sub.1                                                                      methanethiol                                                                           B    11-deoxy-11α-methylthioprostaglandin                                     E.sub.1                                      10   prostaglandin A.sub.1                                                                      1-butanethiol                                                                          B    11-deoxy-11α-butylthioprostaglandin                                     E.sub.1                                       11   13,14-dihydroprosta-                                                                       methanethiol                                                                           B    11-deoxy-11α-methylthio-13,14-dihydr                                    o-                                                 glandin A.sub.1            prostaglandin A.sub.1                         12   13,14-dihydroprosta-                                                                       1-propanethiol                                                                         B    11-deoxy-11α-propylthio-13,14-dihydr                                    o-                                                 glandin A.sub.1            prostaglandin A.sub.1                         __________________________________________________________________________

EXAMPLE 13 Preparation of 11-deoxy-11α/β-15-O-acetylprostaglandin E₂methyl ester

A solution of 5 g. of the methyl ester of 15-O-acetylprostaglandin A₂ in10 ml. of thiolacetate acid is refluxed three hours. The solution isevaporated in vacuo at 45° C. and the residue is dissolved in benzeneand the solution evaporated in vacuo to afford 5.18 g. of an oil. Thinlayer chromatography indicates two compounds (epimers at C-11); λmax1735 cm⁻¹ (saturated carbonyls), 1700 cm⁻¹ ##STR10##

EXAMPLES 14-16

Treatment of the following A type prostaglandins with thiolacetic acidby the procedure of Example 13 affords the 11-acetylthio E-typeprostaglandins of the following table.

    ______________________________________                                               Starting     Product                                                   Example                                                                              Prostaglandin-A                                                                            11-acetylthio-prostaglandin E                             ______________________________________                                        14     Prostaglandin A.sub.2                                                                      11-deoxy-11α/β-acetylthioprosta-                                   glandin E.sub.2                                           15     Prostaglandin A.sub.1                                                                      11-deoxy-11-60 /β-acetylthioprosta-                                      glandin E.sub.1                                           16     13,14-dihydropros-                                                                         11-deoxy-11α/β-acetylthio-13,14-                      taglandin A.sub.1                                                                          dihydroprostaglandin E.sub.1                              ______________________________________                                    

EXAMPLE 17 Preparation of11-deoxy-11α-methyl-15-deoxy-15-methylprostaglandin E₂ methyl ester

To a solution, maintained at -10° C., of lithium dimethyl cuprate (4.87g. cuprous iodide in 10 cc ether titrated with 2 M methyllithium untilthe solution is clear) is added dropwise a solution of 5.0 g. of themethyl ester of 15-O-acetyl-prostaglandin A₂ in 25 ml. of ether. Thesolution is stirred for 15 minutes and then is added to 200 ml. ofsaturated aqueous ammonium chloride. The aqueous solution is extractedwith ether. The ether extracts are combined, washed with brine, driedwith anhydrous magnesium sulfate and evaporated in vacuo to yield 4.65g. of an oil. The oil is purified by silica gel chromatography with 3%ethyl acetate/benene to afford 2.56 g. of the product as an oil; λmax1740 cm⁻¹ (saturated carbonyls); [α]_(D) ²⁵ =-75.4° (C=0.5, chloroform)in addition is obtained 11-deoxy-11α-methyl-15-O-acetylprostaglandin A₂methyl ester.

EXAMPLE 18 Preparation of 11-deoxy-11α-methyl-propstaglandin E₂ methylester

To a -20° C. solution of lithium dimethyl cuprate (prepared from 3.9 gm.cuprous iodide in ten ml. ether by titration with 1 M methyllithiumuntil the resulting solution is clear) is added a solution of 3.36 g. ofthe methyl ester of prostaglandin A₂ (Example 4) in ten ml. of ether.The resulting solution is stirred forty-five minutes and then pouredinto 250 ml. of saturated ammonium chloride and stirred 15 minutes. Thesolution is extracted with ether and the ether extracts are combined,washed with brine, dried with anhydrous magnesium sulfate and evaporatedin vacuo to afford 3.37 g. of an oil that is homogenous by thin layerchromatography; λmax 3400 cm⁻¹ (hydroxyl), 1740 (saturated carbonyls);[α]_(D) ²⁵ =-47.8° (C=0.5, chloroform).

EXAMPLE 19 Preparation of 11-deoxy-11α-vinylprostaglandin E₂ methylester

To a solution of (17.5 mM) lithium divinyl cuprate (prepared from 6.87g. of the cuprous iodide-tributylphosphine complex and 17.5 ml. of 2molar vinyllithium) in tetrahydrofuran at -78° C. is added a solution of3 g. (8.65 mM) of prostaglandin A₂ methyl ester (Example 4) in 10 ml. ofether. The resulting viscous solution is diluted with 10 ml. oftetrahydrofuran and stirred at -78° C. for 60 minutes.

The solution is poured into 150 ml. of saturated aqueous ammoniumchloride and stirred 1 hour at room temperature with 200 ml. of ether.The ether solution is separated and is extracted with water, washed withbrine, dried with magnesium sulfate and evaporated in vacuo to yield12.1 gm. of an oil.

The oil is triturated with methanol several times and the methanolwashes are combined, filtered through celite and evaporated in vacuo toafford 5.9 g. of an oil; λmax: 3400 cm⁻¹ (hydroxyl), 1740 cm⁻¹(saturated ketone and ester), 1635 cm⁻¹ (vinyl group); 970 cm⁻¹ (transdouble bond), 920 cm⁻¹ (terminal vinyl).

EXAMPLES 20-28

Treatment of the A-type prostaglandin methyl esters listed in the tablebelow with the indicated organolithium cuprates and by the indicatedprocedure is productive of the 11-alkyl or 11-alkenyl E-typeprostaglandins of the table.

    __________________________________________________________________________                    Method of                                                                           Starting    Product 11α-alkyl/                    Example                                                                            Cuprate Reagent                                                                          Example                                                                             Prostaglandin Ester                                                                       alkenyl-11-deoxyprostaglandin-E             __________________________________________________________________________    20   diethylcopperlithium                                                                     18    prostaglandin A.sub.2 methyl                                                              11-deoxy-11α-ethylprostaglandin                                         E.sub.2                                                           ester       methyl ester                                21   dipropylcopperlithium                                                                    18    prostaglandin A.sub.2 methyl                                                              11-deoxy-11α-propylprostaglandin                                        E.sub.2                                                           ester       methyl ester                                22   diisopropylcopper-                                                                       18    prostaglandin A.sub.2 methyl                                                              11-deoxy-11α-isopropylprostaglandi                                      n                                                lithium          ester       E.sub.2 methyl ester                        23   dipropenylcopper-                                                                        19    prostaglandin A.sub.2 methyl                                                              11-deoxy-11α-propenylprostaglandin         lithium          ester       E.sub.2 methyl ester                        24   dimethylcopperlithium                                                                    18    prostaglandin A.sub.1 methyl                                                              11-deoxy-11α-methylprostaglandin                                        E.sub.1                                                           ester       methyl ester                                25   diethylcopperlithium                                                                     18    prostaglandin A.sub.1 methyl                                                              11-deoxy-11α-ethylprostaglandin                                         E.sub.1                                                     ester methyl ester                                            26   divinylcopperlithium                                                                     19    prostaglandin A.sub.1 methyl                                                              11-deoxy-11α-vinylprostaglandin                                         E.sub.1                                                     ester methyl ester                                            27   dipropenylcopper-                                                                        19    prostaglandin A.sub.1 methyl                                                              11-deoxy-11α-propenylprostaglandin         lithium          ester       E.sub.1 methyl ester                         28a divinylcopperlithium                                                                     19    13,14-dihydroprostag-                                                                     11-deoxy-11α-vinyl-13,14-dihydropr                                      o-                                                                landin A.sub.1 methyl ester                                                               staglandin E.sub.1 methyl ester              28b divinylcopperlithium                                                                     19    prostaglandin A.sub.2 methyl                                                              11-deoxy-11α-vinylprostaglandin                                         E.sub.2                                                           ester       methyl ester                                __________________________________________________________________________

EXAMPLE 29 Preparation of 11-deoxy-11α-methyl-13,14-dihydroprostaglandinE₁

To a suspension of 300 mg. of 5% rhodium-on-carbon in 10 ml. ofethylacetate is added a solution of 1.02 g. of11-deoxy-11α-methylprostaglandin E₂ (Example 57) in 10 ml. ethylacetate.The resulting suspension is hydrogenated at 50 psi of hydrogen for 1hour. The solution is filtered and the solvent is evaporated in vacuo toafford 1.04 g. of an oil. The oil is purified by dry columnchromatography on a 29"×11/2" flat diameter nylon tube filled with acidwashed silica gel. The column is developed with ethylacetate/benzene/acetic acid (10:40:1) and the section corresponding torf=0.38-0.53 was eluted with 20% methanol in chloroform to afford 542mg. of the product as an oil; λmax 3400 cm⁻¹ (carboxyl and hydroxyl),1740-1710 cm⁻¹ (carboxyl and saturated ketone); [α]_(D) ²⁵ =-49.5(C=0.8, chloroform).

EXAMPLES 30- 32

Treatment of the 11-deoxy-11-alkylprostaglandin E₂ methyl esters listedin the table below by the procedure of Example 29 yields the11α-alkyl-11-deoxy-13,14-dihydro-prostaglandins E₁ of the table.

    ______________________________________                                               Starting      Product - 11α-alkyl-11-deoxy-                      Example                                                                              Prostaglandin-E.sub.2                                                                       13,14-dihydroprostaglandin-E.sub.1                       ______________________________________                                        30     11-deoxy-11α-ethyl-                                                                   11-deoxy-11α-ethyl-13,14-dihy-                            prostaglandin E.sub.2                                                                       droprostaglandin E.sub.1                                 31     11-deoxy-11α-propyl-                                                                  11-deoxy-11α-propyl-13,14-di-                             prostaglandin E.sub.2                                                                       hydroprostaglandin E.sub.1                               32     11-deoxy-11-isopro-                                                                         11-deoxy-11α-isopropyl-13,14-                             pylprostaglandin E.sub.2                                                                    dihydroprostaglandin E.sub.1                             ______________________________________                                    

EXAMPLE 33 Preparation of11-deoxy-11α-dicarboethoxymethyl-15-O-acetyl-prostaglandin E₂ methylester

To a solution of 97 mg. of the methyl ester of 15-O-acetyl-prostaglandinA₂ and 44 mg. of diethylmalonate in one ml. of tetrahydrofuran is addedone drop of a 35% solution of benzyltrimethyl ammonium hydroxide inmethanol. Two ml. of tetrahydrofuran is added and the solution isstirred overnight.

The solution is applied directly to a 2 mm silica-gel thin layerchromatography plate and developed with 20% ethyl acetate/benzene. Theband corresponding to the product is scraped off of the plate and theproduct is isolated by elution off of the silica with 20%methanol/chloroform. The resulting solution is evaporated to afford 76mg. of an oil; λmax 1740 cm⁻¹ (saturated carbonyls), 1225 cm⁻¹ (OAc),1180 and 1020 cm⁻¹ (CO₂ Et), [α]_(D) ²⁵ =-60.98° (C=0.305, chloroform).

EXAMPLE 34 Preparation of11-deoxy-11α-(α,α-dicarboethoxy)methylprostaglandin E₂

To a solution of11-deoxy-11α-(α,α-dicarboethoxy)methyl-15-O-acetyl-prostaglandin E₂methyl ester (Example 33) in methanol is added 2.2 equivalents of a 2.5N aqueous sodium hydroxide solution. The resulting solution is stirredfor 4 hours and then poured into water. Extraction of the aqueoussolution with ether removes unreacted ester. The aqueous solution isacidified and extracted with ether. The ether solution is washed withbrine, dried with magnesium sulfate and evaporated in vacuo to affordthe product. Purification via dry column chromatography affords11-deoxy-11α-(α,α-dicarboethoxy)methylprostaglandin E₂.

EXAMPLE 35 Preparation of11-deoxy-11α-(α,α-dicarboxy)methylprostaglandin E₂

To the product derived from the treatment of 5.5 g. of15-O-acetyl-prostaglandin A₂ methyl ester with diethylmalonate as perExample 33, in 25 ml. of tetrahydrofuran is added 30 ml. of 2.5 Naqueous sodium hydroxide. The solution is stirred overnight at roomtemperature, and is then heated at 80° C. for one hour. The cooledsolution is poured into 50 cc ether and 100 cc water. The aqueous phaseis separated and extracted with ether.

The aqueous phase is acidified with 6 N aqueous hydrochloric acid,saturated with sodium chloride and extracted with ether. The ethersolution is dried with magnesium sulfate and evaporated in vacuo toafford 4.48 g. of nearly pure product; λmax 3400-2600 cm⁻¹ (carboxyl andhydroxyl groups), 1710-1750 cm⁻¹ (saturated ketone and carboxyls).

EXAMPLES 36-38

Treatment of the indicated A-type prostaglandins with the designatedmalonates by the procedure of Example 33 furnishes the products of thetable.

    ______________________________________                                               Reagent    Starting     Product                                        Example                                                                              Malonate   Prostaglandin A                                                                            Prostaglandin E                                ______________________________________                                        36     α-methyldi-                                                                        15-O-acetylprosta-                                                                         11-deoxy-11α-(α,α-                  ethylmalonate                                                                            glandin A.sub.2 methyl                                                                     dicarboethoxy                                                    ester        ethyl-15-O-acetyl-                                                            prostaglandin E.sub.2                                                         methyl ester                                   37     α-ethyldieth-                                                                      15-O-acetylprosta-                                                                         11-deoxy-11α-(α,α-                  ylmalonate glandin A.sub.2 methyl                                                                     dicarboethoxy                                                    ester        propyl-15-O-acetyl-                                                           prostaglandin E.sub.2                                                         methyl ester                                   38     diethyl-   prostaglandin A.sub.1                                                                      11-deoxy-11α-(α,α-                  malonate   methyl ester dicarboethoxy                                                                 methylprostaglandin                                                           E.sub.1 methyl ester                           ______________________________________                                    

EXAMPLE 39 Preparation of11-deoxy-11α-nitromethyl-15-O-acetylprostaglandin E₂ methyl ester

To a solution of 15.1 g. of the methyl ester of 15-O-acetylprostaglandinA₂ in 15 ml. of tetrahydrofuran is added a solution of 15 ml.nitromethane containing 1 ml. of a 35% solution of triton B(benzyl-trimethyl ammonium hydroxide) in methanol. The solution isstirred for one hour and is then poured into a mixture of 75 ml. ofwater and 70 ml. of ether. One ml. of 6 N aqueous hydrochloric acid isadded and the aqueous layer is extracted with ether. The ether extractsare combined, washed with brine, dried (anhydrous magnesium sulfate) andevaporated in vacuo to afford 17.5 g. of an oil that can be purified bydry column chromatography; λmax 1740 cm⁻¹ (saturated carbonyls), 1555cm⁻¹ (NO₂), 1375 cm⁻¹ (NO₂), 1225 cm⁻¹ (OAc), [α]_(D) ²⁵ =-45.5,(C=0.530, chloroform).

EXAMPLES 40-45

Treatment of the indicated A-type prostaglandins with the designatednitroalkanes via the procedure of Example 39 is productive of theproducts of the following table.

    ______________________________________                                                                       Product - 11-deoxy-                            Exam- Reagent     Starting     11α-(nitroalkyl)-                        ple   Nitroalkane Prostaglandin A                                                                            prostaglandin E                                ______________________________________                                        40    nitroethane 15-O-acetylprosta-                                                                         11-deoxy-11α -(α-ni-                                 glandin A.sub.2 methyl                                                                     troethyl)-15-O-ace-                                              ester        tylprostaglandin E.sub.2                                                      methyl ester                                   41    2-nitropropane                                                                            15-O-acetylpros-                                                                           11-deoxy-11α-(α-                                     taglandin A.sub.2                                                                          nitro, α-methyl-                                           methyl ester ethyl)-15-O-acetyl-                                                           prostaglandin E.sub.2                                                         methyl ester                                   42    1-nitropropane                                                                            15-O-acetylpros-                                                                           11-deoxy-11α-(α-                                     taglandin A.sub.2                                                                          nitropropyl)-15-                                                 methyl ester O-acetylprostaglan-                                                           din E.sub.2 methyl ester                       43    nitromethane                                                                              prostaglandin A.sub.1                                                                      11-deoxy-11α-nitro-                                        methyl ester methyl prostaglan-                                                            din E.sub.1 methyl ester                       44    nitroethane prostaglandin A.sub.1                                                                      11-deoxy-11α-(α-                                     methyl ester nitroethyl)prosta-                                                            glandin E.sub.1 methyl                                                        ester                                          45    nitromethane                                                                              13,14-dihydropros-                                                                         11-deoxy-11α-nitro-                                        taglandin A.sub.1                                                                          methyl-13,14-dihy-                                               methyl ester droprostaglandin E.sub.1                                                      methyl ester                                   ______________________________________                                    

EXAMPLE 46 Preparation of 11-deoxyprostaglandin E₂ methyl ester

To a suspension of 300 mg. potassium carbonate in 30 ml. of methanol isadded 11-deoxy-15-O-acetyl-prostaglandin E₂ methyl ester (Example 96) inone ml. of methanol. The solution is stirred for 48 hours and is thenacidified with 6 N aqueous hydrochloric acid. The solution is dilutedwith water and extracted with ether. The ether solution is washed withbrine, dried with magnesium sulfate and evaporated in vacuo to yield 540mg. of crude product. The product is purified by dry columnchromatography using acid washed silica gel and eluting with 20%ethylacetate in benzene; λmax: 3400 cm⁻¹ (hydroxyl), 1735 cm⁻¹(saturated ketone and ester).

EXAMPLE 47 Preparation of 11-deoxy-11α-nitromethyl prostaglandin E₂

To a solution of 11.54 g. of the methyl ester of11-deoxy-11α-nitromethyl-15-O-acetyl-prostaglandin E₂ (Example 39) in 40ml. of methanol is added 45 ml. of a 2.5 N sodium hydroxide solution andthe resulting solution is stirred at room temperature for 2 hours. Thesolution is poured into 100 ml. of ether and 100 ml. of water. Theaqueous layer is separated and extracted with ether. The aqueous layeris covered with ether and acidified with 23 ml. of 6 N aqueoushydrochloric acid. The acidic solution is saturated with sodium chlorideand extracted with ether. The ether is dried with magnesium sulfate andevaporated in vacuo to give 10.3 g. of a viscous oil that is purified bydry column chromatography on acid washed silica gel; λmax 3600-3400 cm⁻¹(hydroxyl and carboxyl), 1735 cm⁻¹ (saturated carbonyl), 1700 cm⁻¹(carboxyl), 1550 cm⁻¹ (nitro); [α ]_(D) ²⁵ =-41.5° (C=1.0, chloroform).

EXAMPLES 48-67

Saponification of the prostaglandin esters listed in the table by theindicated procedures yields the product prostaglandin acids of thefollowing table.

    ______________________________________                                        Exam- Starting Pros-                                                          ple   taglandin Ester                                                                           Method of Product Acid                                      ______________________________________                                        48    Example 36  Example 34                                                                              11-deoxy-11α-(α,α-di-                                       carboethoxyethyl)pro-                                                         staglandin E.sub.2                                49    Example 37  Example 34                                                                              11-deoxy-11α-(α,α-di-                                       carboethoxypropyl)-                                                           prostaglandin E.sub.2                             50    Example 38  Example 34                                                                              11-deoxy-11α-(α,α-di-                                       carboethoyxmethyl)-                                                           prostaglandin E.sub.1                             51    Example 40  Example 47                                                                              11-deoxy-11α-(α-nitro-                                            ethyl)prostaglandin E.sub.2                       52    Example 41  Example 47                                                                              11-deoxy-11α-(α-nitro,                                            α-methylethyl)prosta-                                                   glandin E.sub.2                                   53    Example 42  Example 47                                                                              11-deoxy-11α-(α-nitro-                                            propyl)prostaglandin E.sub.2                      54    Example 43  Example 47                                                                              11-deoxy-11α-nitrome-                                                   thyl prostaglandin E.sub.1                        55    Example 44  Example 47                                                                              11-deoxy-11α-(α-nitro-                                            ethyl)prostaglandin E.sub.1                       56    Example 45  Example 47                                                                              11-deoxy-11α-nitrometh-                                                 yl-13,14-dihydroprosta-                                                       glandin E.sub.1                                   57    Example 18  Example 47                                                                              11-deoxy-11α-methyl-                                                    prostaglandin E.sub.2                             58    Example 19  Example 47                                                                              11-deoxy-11α-vinyl-                                                     prostaglandin E.sub.2                             59    Example 20  Example 47                                                                              11-deoxy-11α-ethyl-                                                     prostaglandin E.sub.2                             60    Example 21  Example 47                                                                              11-deoxy-11α-propyl-                                                    prostaglandin E.sub.2                             61    Example 22  Example 47                                                                              11-deoxy-11α-isopropyl-                                                 prostaglandin E.sub.2                             62    Example 23  Example 47                                                                              11-deoxy-11α-pentyl-                                                    prostaglandin E.sub.2                             63    Example 24  Example 47                                                                              11-deoxy-11α-methyl-                                                    prostaglandin E.sub.1                             64    Example 25  Example 47                                                                              11-deoxy-11α-ethylpros-                                                 taglandin E.sub.1                                 65    Example 26  Example 47                                                                              11-deoxy-11α-vinylpros-                                                 taglandin E.sub.1                                 66    Example 27  Example 47                                                                              11-deoxy-11α-propenyl-                                                  prostaglandin E.sub.1                             67    Example 28  Example 47                                                                              11-deoxy-11α-vinyl-13,14-                                               dihydroprostaglandin E.sub.1                       67a   Example 173                                                                              Example 47                                                                              11-deoxy-11α-(1-hydroxy-                                                1-methylethyl)-prosta-                                                        glandin E.sub.2                                   ______________________________________                                    

EXAMPLE 68 Preparation of11α/11β-cyano-11-deoxy-15-O-acetyl-prostaglandin E₂ methyl ester

To a solution of 9.4 g. of the methyl ester of15-O-acetyl-prostaglandin-A₂ in a mixtuure of 10 ml. acetonecyanohydrinand 10 ml. methanol is added 1 ml. of 5% aqueous sodium carbonate. Theresulting solution is refluxed overnight and after cooling, poured intocold water and extracted with ether. The combined ether extracts arewashed with brine and dried with anhydrous magnesium sulfate andevaporated in vacuo to give 12.3 g. of an oil.

The material is redissolved in benzene and washed with water to removeacetonecyanohydrin. The benzene solution is dried with magnesium sulfateand evaporated in vacuo. The material is purified by dry columnchromatography to afford 8.5 g. of subject compound as an oil; λmax 2220cm⁻¹ (nitrile), 1735 cm⁻¹ (saturated carbonyls); [α]_(D) ²⁵ =-56.23°,(C=0.918, chloroform).

EXAMPLES 69-70

Treatment of the listed A-type prostaglandins by the procedure ofExample 68 is productive of the 11α/β-cyano products of the followingtable.

    ______________________________________                                                Starting      Product 11α/β-11-deoxy-                      Example Prostaglandin-A                                                                             prostaglandin-E                                         ______________________________________                                        69      prostaglandin A.sub.1                                                                       11α/β-cyano-11-deoxyprosta-                                        glandin E.sub.1                                         70      13,14-dihydropros-                                                                          11α/β-cyano-11-deoxy-13,14-                          taglandin A.sub.1                                                                           dihydroprostaglandin E.sub.1                            ______________________________________                                    

EXAMPLE 71 Preparation of 11α/β-cyano-11-deoxy-prostaglandin E₂

To a solution of 3 g. of the methyl ester of11α/β-cyano-11-deoxy-15-O-acetyl-prostaglandin E₂ (Example 68) in 36 ml.of methanol is added 12 ml. of an aqueous saturated solution of sodiumcyanide. The solution is stirred for 96 hours and then poured into 100ml. of ether. 20 ml. of water is added and the ether is extracted twicewith 15 ml. 5% aqueous sodium bicarbonate. The combined aqueous extractsare acidified to pH 3 with 6 N aqueous hydrochloric acid, saturated withsodium chloride, and extracted with ether. The ether extracts arecombined, dried with magnesium sulfate, and evaporated in vacuo toafford 1.64 g. of 11α/β-cyano-11-deoxyprostaglandin E₂ as an oil; λmax3400 cm⁻¹ (carboxyl, hydroxyl), 2220 cm⁻¹ (nitrile), 1735 cm⁻¹(saturated carbonyl), 1700 cm⁻¹ (carboxyl).

The first ether extract is dried with magnesium sulfate and evaporatedin vacuo to afford 0.8 g. of 11α/β-cyano-11-deoxyprostaglandin E₂ methylester as an oil; λmax 3400 cm⁻¹ (hydroxyl), 2220 cm⁻¹ (nitrile), 1735cm⁻¹ (saturated carbonyl, ester).

EXAMPLES 72-73

Ester hydrolysis of the following compounds by this procedure of Example71 yields the products of the following table.

    ______________________________________                                               Starting   Product 11α/β-cyano-11-deoxyprosta-              Example                                                                              Prostaglandin                                                                            glandin E                                                   ______________________________________                                        72     Example 69 11α/β-cyano-11-deoxyprostaglan-                                    din E.sub.1                                                 73     Example 70 11α/β-cyano-11-deoxy-13,14-dihydro-                                prostaglandin E.sub.1                                       ______________________________________                                    

EXAMPLE 74 Preparation of 11α/β-carboxamido-11-deoxy-15-O-acetylprostaglandin E₂ methyl ester

To a solution of 5.04 g. of the methyl ester of11α/β-cyano-11-deoxy-15-O-acetylprostaglandin E₂ (Example 68) in 10 ml.of ethanol, 10 ml. tetrahydrofuran and 10 ml. cyclohexene is added asolution consisting of 1.5 ml. of 25% methanolic tetramethylammoniumhydroxide in 7.0 ml. of 30% hydrogen peroxide. The resulting solution isheated to 60° C. for one hour and then stirred 48 hours at roomtemperature. One drop of methyltricaprylammonium chloride is added andthe solution is heated for 2 hours at 55° C. The solution is cooled andpoured into 100 ml. ether and 100 ml. water. The aqueous layer isextracted with ether. The ether extracts are combined, dried withanhydrous magnesium sulfate and evaporated in vacuo to give 4.96 g. ofan oil. The oil is purified by dry column chromatography on a 20"×1/4"column of silica gel and developed with 20% ethyl acetate in benzene togive 2.5 g. of the product carboxamide as an oil; λmax 3400-3600 cm⁻¹(NH₂ of carboxamide), 1735 cm⁻¹ (saturated ketone and esters), 1675 cm⁻¹(carboxamide carbonyl), 1620 cm⁻¹ (carboxamide), 1220 cm⁻¹ (acetate),1180 cm⁻¹ (methyl ester); [α]_(D) ²⁵ =-114.7° (C=0.63, chloroform).

EXAMPLE 75 Preparation of 11α-carboxamido-11-deoxyprostaglandin E₂

To a solution of 1.41 g. of11α/β-carboxamido-11-deoxy-15-O-acetylprostaglandin E₂ methyl ester(Example 74) in 5 ml. of methanol is added 2.8 ml. of a 2.5 N aqueoussodium hydroxide solution and 2.2 ml. of water. The solution is stirredovernight and poured into 50 ml. of ether and 50 ml. of water. The wateris extracted with ether and the ether solutions are discarded. Theaqueous solution is acidified to pH 2 with 6 N aqueous hydrochloric acidand saturated with sodium chloride. The aqueous solution is extractedwith ether; the ethereal solution is dried with magnesium sulfate andthe ether is evaporated in vacuo to yield 1.1 g. of the product as anoil; λmax: 3400 cm⁻¹ (carboxyl, hydroxyl, and amido hydrogens), 1740cm⁻¹ (saturated ketone), 1710 cm⁻¹ (amide carbonyl); [α]_(D) ²⁵ =-25°(C=-76 chloroform, acetone).

EXAMPLE 76 Preparation of 11α-carboxy-11-deoxyprostaglandin E₂

To a solution of 737 mg. of11α-carboxamido-11-deoxy-15-O-acetylprostaglandin E₂ methyl ester(Example 74) in 5 ml. of methanol is added dropwise 5 ml. of a 2.5 Naqueous sodium hydroxide solution. The solution is heated at 80° C. fortwo hours and an additional 5 ml. of 2.5 N aqueous sodium hydroxide thenis added and the solution is heated at 80° C. for 15 hours. The solutionis cooled and extracted with ether. The aqueous solution is acidifiedwith 6 N aqueous hydrochloric acid and extracted with ether. Theethereal solution is washed with brine, dried with magnesium sulfate andevaporated in vacuo to yield 520 mg. of the crude product; λmax:3400-2700 cm⁻¹ (hydroxyl and carboxyl groups), 1740-1710 cm⁻¹ (saturatedketone and carboxyl groups).

EXAMPLES 77-79

Hydrogenation of the listed prostaglandin E₂ derivative by the procedureof Example 29 furnishes the product 13,14-dihydroprostaglandin E₁ of thefollowing table.

    ______________________________________                                               Starting                                                                      11-substituted-                                                                             Product 11-substituted-                                  Example                                                                              prostaglandin E.sub.2                                                                       13,14-dihydroprostaglandin E.sub.1                       ______________________________________                                        77     Example 74    11α-carboxamido-11-deoxy-                                               13,14-dihydro-15-O-acetyl                                                     prostaglandin E.sub.1 methyl                                                  ester                                                    78     Example 75    11α-carboxamido-11-deoxy-                                               13,14-dihydroprostaglan-                                                      din E.sub.1                                              79     Example 76    11α-carboxy-11-deoxy-                                                   13,14-dihydroprostaglan-                                                      din E.sub.1                                              ______________________________________                                    

EXAMPLE 80 Preparation of 11-deoxy-11α-methyl-prostaglandin F₂α

To a -78° C. solution of 877 mg. 11-deoxy-11α-methylprostaglandin E₂(Example 57) in 8 ml. tetrahydrofuran is added 9.8 ml. of 0.66 M lithiumperhydro-9-b-boraphenalyl hydride in tetrahydrofuran. The solution isstirred for 30 minutes and then 15 ml. of water is added and the dry-icebath is removed. The solution is poured into 20 ml. of water andextracted with ether. The combined ether extracts are washed with 5%sodium bicarbonate. The combined aqueous solutions are acidified with 6N hydrochloric acid, saturated with sodium chloride and extracted withether. The ether is dried with anhydrous magnesium sulfate andevaporated in vacuo to an oil; λmax 3400 cm⁻¹ (OH), 1700 cm⁻¹ (COOH);420 Hz (2H) 15-H and 9β-H; [α]_(D) ²⁵ =+15° (C=0.4, chloroform).

EXAMPLE 81 Preparation of 11α-carboxamido-11-deoxyprostaglandin F₂α

To a -78° C. solution of 1.59 g. of the methyl ester of11α-carboxamido-11-deoxy-15-O-acetyl-prostaglandin E₂ (Example 75) in 10ml. tetrahydrofuran is added 7.35 ml. of 0.65 M lithiumperhydro-9-b-boraphenalyl hydride in tetrahydrofuran. The solution isstirred for 60 minutes at -78°, then stirred at room temperature for 20minutes. The tetrahydrofuran is evaporated in vacuo at 25° C. Theresidue is dissolved in 2 ml. methanol, 6 ml. water and 4 ml. of 2.5 Naqueous sodium hydroxide and stirred 3 hours at room temperature. Thesolution containing the11-carboxamido-11-deoxy-15-O-acetyl-prostaglandin E₂ methyl ester ispoured into 50 ml. of water and extracted with ether. The ether solutionis washed with 5% aqueous sodium bicarbonate and combined with theaqueous solution. The combined aqueous solution is acidified with 6 Naqueous hydrochloric acid, saturated with sodium chloride, and extractedwith ether. The ether is dried with magnesium sulfate and evaporated invacuo to afford 1.48 g. of a viscous oil; λmax, 3400 cm⁻¹ (OH, NH₂,COOH), 1700 cm⁻¹ (COOH), 1660 cm⁻¹ (CONH₂); 405 Hz (15-H, 9β-H); [α]_(D)²⁵ =+8.2° (C=0.65, chloroform).

EXAMPLES 82-89

Carbonyl reduction of the listed prostaglandin E derivatives by theprocedure of the example designated furnishes the product prostaglandinF.sub.α, of the following table.

    ______________________________________                                               Starting 11-sub-                                                              stituted prosta-     Product 11-substituted-                           Example                                                                              glandin E   Method   prostaglandin F                                   ______________________________________                                        82     Example 21  81       11α-propyl-11-deoxypros-                                                taglandin F.sub.2α                          83     Example 22  81       11α-isopropyl-11-deoxy-                                                 prostaglandin F.sub.2α                      84     Example 6   80       11α-methylthio-11-deoxy-                                                prostaglandin F.sub.2α and                                              11α-methylthio-11-deoxy-                                                prostaglandin-F.sub.2β                       85     Example 39  81       11α-nitromethyl-11-deoxy-                                               prostaglandin F.sub.2α and 11α -                                  nitromethyl-11-deoxy-                                                         prostaglandin F.sub.2β                       86     Example 35  80       11α-dicarboxymethyl-11-                                                 deoxyprostaglandin F.sub.2α                 87     Example 25  81       11α-ethyl-11-deoxyprosta-                                               glandin F.sub.1α                            88     Example 38  81       11α-(α,α-dicarboethoxy)-                                    methyl-11-deoxyprosta-                                                        glandin F.sub.1α                            89     Example 29  80       11α-methyl-11-deoxy-                                                    13,14-dihydroprostaglan-                                                      din F.sub.1α                                ______________________________________                                    

EXAMPLE 90 Conversion of 11α-methyl-11-deoxyprostaglandin E₂ to11α-methyl-11-deoxyprostaglandin F₂α and11α-methyl-11-deoxyprostaglandin F₂β

To a solution of 11α-methyl-11-deoxyprostaglandin E₂ in methanol at 0°C. is added 1 molar equivalent of sodium borohydride. After 60 minutesthe solution is poured into water, acidified to pH=3 with 6 Nhydrochloric acid, saturated with sodium chloride and extracted withether. The ethereal solution is dried with magnesium sulfate and theether is evaporated in vacuo to afford a mixture of11α-methyl-11-deoxyprostaglandin F₂α and11α-methyl-11-deoxyprostaglandin F₂β.

EXAMPLES 91-95

Carbonyl reduction of the listed 11-substituted prostaglandin (E type)by the method of Example 90 is productive of the 11-substitutedprostaglandins (F type) of the table.

    ______________________________________                                               Starting 11-substi-                                                                         Product 11-substituted prosta-                           Example                                                                              tuted prostaglandin                                                                         glandin Fα/β                                  ______________________________________                                        91     Example 29    11α-methyl-11-deoxy-13,14-di-                                           hydroprostaglandin F.sub.1α /F.sub.2β         92     Example 51    11α-(α-nitroethyl)-11-deoxy-                                      prostaglandin F.sub.2α /F.sub.2β              93     Example 65    11α-vinyl-11-deoxyprostaglan-                                           din F.sub.1α /F.sub.2β                        94     Example 75    11α-carboxamido-11-deoxypros-                                           taglandin F.sub.2α /F.sub.2β                  95     Example 66    11α-propenyl-11-deoxyprosta-                                            glandin F.sub.1α /F.sub.1β                    ______________________________________                                    

EXAMPLE 96 Preparation of 11-deoxyprostaglandin E₂ from 15-O-acetylprostaglandin A₂ methyl ester

To a solution of 1.04 g. of 15-O-acetylprostaglandin A₂ methyl ester in5 ml. of methanol is added a solution of 209 mg. of sodiumcyanoborohydride in 2 ml. of methanol. The solution is adjusted to pH 3with 2 N methanolic hydrogen chloride and maintained at this pH byaddition of methanolic hydrochloric acid as necessary. After 90 minutesthe solution is evaporated in vacuo, 5 ml. of water is added. Thesolution is saturated with sodium chloride and extracted with ether. Theether extracts are dried with magnesium sulfate and evaporated in vacuoto yield 1.02 g. of an oil consisting mainly of11-deoxy-15-O-acetyl-prostaglandin F₂α /F₂β methyl esters.

To a solution of 900 mg. of the above mixture of11-deoxy-15-O-acetyl-prostaglandin F₂α /F₂β methyl esters in 30 ml. ofacetone at 0° C. is added 0.8 ml. of a standard chromic acid solution.The solution is stirred 10 minutes and poured into 70 ml. of ice andwater. The aqueous solution is extracted with ether. The ether solutionis dried with magnesium sulfate and evaporated in vacuo to afford 830mg. of 11-deoxy-15-O-acetyl-prostaglandin E₂ methyl ester as an oil.

To a solution of 11-deoxy-15-O-acetyl-prostaglandin E₂ methyl ester inmethanol is added 4 equivalents of 2.5 N aqueous sodium hydroxide. Thesolution is stirred for 3 hours, poured into water, saturated withsodium chloride and acidified with 6 N aqueous hydrochloric acid to pH3.

The acidic solution is extracted with ether. The ethereal extracts aredried with magnesium sulfate and evaporated in vacuo to afford11-deoxyprostaglandin E₂ ; λmax: 3400-2700 cm⁻¹ (carboxyl and hydroxyl),1745-1710 cm⁻¹ (saturated ketone and carboxyl groups).

EXAMPLE 97 Epimerization of 11-deoxyprostaglandin E₂ methyl ester

To a solution of 24 mg. of 11-deoxyprostaglandin E₂ methyl ester(Example 46) in 0.5 ml. of methylenechloride at -5° C. is added 15 μl oftriethylamine followed by 28 mg. of methanesulfonic acid anhydride in0.5 cc methylenechloride. The solution is stirred at -5° C. for 30minutes and then all solvents are removed in vacuo.

The residue is dissolved in 5 ml. of ether and the ether solution isadded to a flask containing 245 mg. of tetraethylammonium formate. Theether is evaporated in vacuo at -5° C. and replaced by 2 cc of dryacetone. The solution is maintained at 10° C. for 18 hours. The acetoneis removed in vacuo and the residue is dissolved in 10 cc ether. Theether solution is washed with 5 ml. of 5% aqueous sodium bicarbonatesolution and 5 ml. of brire. The ether solution is dried with magnesiumsulfate and the ether evaporated in vacuo to yield 26.7 mg. of11-deoxy-15R-O-formylprostaglandin E₂ methyl ester as an oil.

Treatment of a solution of the 11-deoxy-15R-O-formylprostaglandin E₂methyl ester in 0.5 ml. of methanol with a crystal of p-toluenesulfonicacid overnight yields 15R-11-deoxyprostaglandin E₂ methyl ester as asoil that chromatographs slightly ahead of the starting15S-11-deoxyprostaglandin E₂ methyl ester on silica gel. The residuealso contains some of the starting 15S material.

EXAMPLE 98 Racemization of 15S-11-deoxyprostaglandin E₂ methyl ester

To 13 mg. of 15S-11-deoxyprostaglandin E₂ methyl ester (Example 46) isadded a solution of 5 mg. potassium carbonate in 0.5 ml. of 97% formicacid. The solution is stirred under nitrogen for 60 minutes. Benzene isadded and the solution is evaporated in vacuo.

The residue is placed on a 2 mm silica gel plate and developed with 20%ethylacetate in benzene. The area corresponding to rf=0.45-0.65 isremoved and the compound is eluted off of the silica-gel with 20%methanol in chloroform. The silica-gel is filtered and the organicsolvents are evaporated in vacuo to yield 9 mg. of a mixture of11-deoxy-15-O-formylprostaglandin E₂ methyl ester and the corresponding15R epimer.

The mixture of 15-O-formyl compounds is dissolved in 1 ml. of methanoland one small crystal of p-toluenesulfonic acid is added. The solutionis stirred overnight to afford approximately a 1:1 mixture of15S-11-deoxyprostaglandin E₂ methyl ester and 15R-11-deoxyprostaglandinE₂ methyl ester.

Thin layer chromatography on silica-gel indicates the newly formedepimer (15R) is slightly less polar than the starting (15S) epimer.

EXAMPLE 99 Conversion of 11-deoxy-11α-nitromethylprostaglandin E₂ to11-deoxy-11-formylprostaglandin E₂

A solution of 208 mg. 11-deoxy-11α-nitromethylprostaglandin E₂ (Example47) in 5.5 ml. of 0.21 N aqueous sodium hydroxide is added dropwise to avery rapidly stirred solution of 0.5 ml. 6 N hydrochloric acid in 5 ml.methanol. The solution is poured into 30 ml. of ether and 25 ml. ofbrine is added. The ether extracts are washed with brine, dried withmagnesium sulfate and evaporated in vacuo to afford 167 mg. of a viscousoil. Purification by dry column chromatography using ethylacetate/benzene/acetic acid for development followed by elution from thesilica-gel with 20% methanol/chloroform affords the product as a mixtureof 11-formyl-11-deoxyprostaglandin E₂ and the corresponding acetyl,11-dimethoxymethyl-11-deoxyprostaglandin E₂.

EXAMPLE 100 Conversion of11-deoxy-11α-(α,α-dicarboxy)methylprostaglandin E₂ to11-deoxy-11α-carboxymethylprostaglandin E₂

A solution of 11-deoxy-11α-(α,α-dicarboxy)methylprostaglandin E₂(Example 35) is dissolved in xylene and heated until carbon dioxideevolution begins. The solution is maintained at that temperature untilthe starting material has been consumed (thin layer chromatographyevidence). The xylene solution is evaporated in vacuo to afford theproduct.

EXAMPLE 101 Preparation of11α-(β-dimethylaminoethylthio)-11-deoxy-15-O-acetyl-prostaglandin A₂methyl ester

A solution of 164 mg. of 2-diethylaminoethanethiol hydrochloride in 1ml. of methanol containing 6 drops of a 5% aqueous sodium bicarbonatesolution (pH˜8) is added to a solution of 104 mg.15-O-acetylprostaglandin A₂ methyl ester in 1 ml. of methanol. Thesolution is stirred twenty minutes and then evaporated in vacuo to apaste. The paste was dissolved in 20 ml. of ether and 20 ml. of water. Asmall amount of sodium chloride is added to break up the emulsionformed. The aqueous layer is extracted with ether. The ether extractsare dried with magnesium sulfate and the ether is evaporated in vacuo toafford the product as an oil; λmax: 1745 cm⁻¹ (saturated ketone andesters), 1240 cm⁻¹ (acetate).

EXAMPLE 102 Preparation of 11-mercapto-15-O-acetylprostaglandin F₂ αmethyl ester

To a solution of 1.0 g. of 11-acetylthio-11-deoxy-15-O-acetylprostaglandin A₂ methyl ester in 4 ml. of tetrahydrofuran maintained at-78° C. is added a solution of 0.65 M lithium perhydro-9-b-boraphenalylhydride in tetrahydrofuran. The solution is stirred at -78° C. for 1hour. The solution is then poured into 50 ml. of ether and 50 ml. ofwater and the aqueous layer is saturated with sodium chloride.

The aqueous layer is extracted with ether and the combined etherextracts are dried with magnesium sulfate and the ether is evaporated invacuo to afford 1.7 g. of residue. Trituration of the residue withbenzene/hexane followed by filtration and evaporation of the organicsolvents affords 1.1 g. of crude product. The material is purified bypartition chromatography to afford 150 mg. of11-mercapto-11-deoxy-15-O-acetyl prostaglandin F₂α methyl ester.

EXAMPLE 103 Preparation of 1 20-ethyl prostaglandin A₂

A solution of 120-ethyl-9-oxo-11,15(S)-bis-(tetrahydropyran-2-yloxy)-5-cis-13-trans-prostadienoicacid [Patent No. 2,150,361 (West Germany, 1972)] in tetrahydrofurancontaining 1.5 N hydrochloric acid is kept at ambient temperature for 70hours. The solution is flooded with saturated sodium chloride andextracted several times with ether. The combined extracts are washedwith water, dried with anhydrous magnesium sulfate and taken to drynessto afford the subject compound.

EXAMPLES 104-114

The prostaglandins E of the table below when treated in the manner ofExample 103 furnish the corresponding prostaglandins A.

    __________________________________________________________________________    Example                                                                            Starting Prostaglandins E                                                                        Product Prostaglandins A                              __________________________________________________________________________    104  l-17,20-tetranor-16-m-chlorophenoxy-                                                             l-17,20-tetranor-16-m-chlorophenoxy-                       prostaglandin-E.sub.2.sup.a                                                                      prostaglandin-A.sub.2                                 105  l-17,20-tetranor-16-phenoxyprosta-                                                               l-17,20-tetranor-16-phenoxyprosta-                         glandin-E.sub.2.sup.a                                                                            glandin-A.sub.2                                       106  l-17,20-tetranor-16-p-fluorophenoxy-                                                             l-17,20-tetranor-16-p-fluorophenoxy-                       prostaglandin-E.sub.2.sup.a                                                                      prostaglandin-A.sub.2                                 107  l-17,20-tetranor-16-m-trifluoro-                                                                 l-17,20-tetranor-16-m-trifluoro-                           methylphenoxyprostaglandin-E.sub.2.sup.a                                                         methylphenoxyprostaglandin-A.sub.2                    108  l-20-methylprostaglandin-E.sub.2.sup.b                                                           l-20-methylprostaglandin-A.sub.2                      109  l-prostaglandin-E.sub.3 - E. J. Corey, et al.                                                    l-prostaglandin-A.sub.3                                    Journ. Amer. Chem. Soc., 93, 1490                                             (1971)                                                                   110  dl-prostaglandin-E.sub.2                                                                         dl-prostaglandin-A.sub.2                                   E. J. Corey, et al., Journ. Amer.                                             Chem. Soc., 91, 5675 (1969)                                              111  dl-17,20-tetranor-16-m-chlorophenoxy-                                                            dl-17,20-tetranor-16-m-chlorophenoxy-                      prostaglandin-E.sub.2.sup.c                                                                      prostaglandin-A.sub.2                                 112  dl-17,20-tetranor-16-phenxoyprosta-                                                              dl-17,20-tetranor-16-phenoxyprosta-                        glandin-E.sub.2.sup.c                                                                            glandin-A.sub.2                                       113  dl-17,20-tetranor-16-p-fluoro-                                                                   dl-17,20-tetranor-16-p-fluorophenoxy-                      phenoxyprostaglandin-E.sub.2.sup.c                                                               prostaglandin-A.sub.2                                 114  dl-17,20-tetranor-16-m-trifluoromethyl-                                                          dl-17,20-tetranor-16-m-trifluoromethyl-                    prostaglandin-E.sub.2.sup.c                                                                      phenoxyprostaglandin-A.sub.2                          __________________________________________________________________________     References:                                                                   .sup.a D. Binder et al., Prostaglandins, Vol. 6, No. 1, 87 (1974).            .sup.b D. van Dorp, Annal of the New York Academy of Sciences, Volume 180     181 (1971).                                                                   .sup.c Netherlands Patent No. 7,206,361, May 11, 1971.                   

EXAMPLES 115-129

Treatment of the A type prostaglandins, listed in the table below, withthe listed alkyl mercaptans in the manner of Example 2 (method A) orExample 3 (method B) is productive of the 11α-alkylthioprostaglandins ofthe table.

    __________________________________________________________________________         Starting   Alkyl          Product 11α-alkylthio-                   Example                                                                            Prostaglandin A                                                                          Reagent Mercaptan                                                                       Method                                                                             11-deoxyprostaglandin E                        __________________________________________________________________________    115  l-prosataglandin-A.sub.3                                                                 Ethanethiol                                                                             B    l-11-deoxy-11α-ethylthioprostaglandin                                   -                                                   (Example 109)             E.sub.3                                        116  l-15-epiprosta-                                                                          Methanethiol                                                                            B    l-11-deoxy-11α-methylthio-15-epi-pros                                   ta-                                                 glandin-A.sub.2           glandin-E.sub.2                                117  l-15-epi-O-acetyl-                                                                       1-propanethiol                                                                          A    l-11-deoxy-11α-(1-propylthio)-15-             prostaglandin-A.sub.2     epi-O-acetylprostaglandin-E.sub.2                   methyl ester              methyl ester                                   118  dl-prostaglandin-A.sub.1                                                                 1-butanethiol                                                                           B    dl-11-deoxy-11α-butylthioprostaglandi                                   n                                                                             E.sub.1                                        119  l-15-methylprosta-                                                                       methanethiol                                                                            B    l-11-deoxy-11α-methylthiolprosta-             glandin-A.sub.1 methyl    glandin-E.sub.1 methyl ester                        ester                                                                    120  l-15-methylprosta-                                                                       ethanethiol                                                                             B    l-11-deoxy-11α-ethylthio-15-methyl-           glandin-A.sub.2 methyl    prostaglandin-E.sub.2 methyl ester                  ester                                                                    121  l-16,16-dimethyl-                                                                        1-propanethiol                                                                          B    l-11-deoxy-11α-propylthiol-16,16-di-          prostaglandin-A.sub.2     methylprostaglandin-E.sub.2                    122  l-16(S)-methyl-                                                                          ethanethiol                                                                             B    l-11-deoxy-11α-ethylthio-16(S)-methyl                                   -                                                   prostaglandin-A.sub.2     prostaglandin-E.sub.2                          123  l-16,16-difluoro-                                                                        Methanethiol                                                                            B    l-11-deoxy-11α-methylthio-16,16-              prostaglandin-A.sub.2     difluoroprostaglandin-E.sub.2                  124  l-16-fluoroprosta-                                                                       Methanethiol                                                                            B    l-11-deoxy-11α-methylthio-16-                 glandin-A.sub.2           fluoroprostaglandin-E.sub.2                    125  l-20-ethylprosta-                                                                        Methanethiol                                                                            B    l-11-deoxy-11α-methylthiol-20-                glandin-A.sub.2 (EX. 103) ethylprostaglandin-E.sub.2                     126  dl-17,20-tetranor-                                                                       Ethanethiol                                                                             B    dl-11-deoxy-11α-ethylthio-17,20-              16-p-fluoro-              tetranor-16-p-fluorophenoxy-                        phenoxyprostaglan-        prostaglandin-E.sub.2                               din-A.sub.2 (EX. 113)                                                    127  dl-17,20-tetranor-                                                                       Methanethiol                                                                            B    dl-11-deoxy-11α-methylthio-17,20-             16-m-trifluoro-           tetranor-16-m-trifluoromethyl-                      methylphenoxy-            phenoxyprostaglandin-E.sub.2                        prostaglandin-A.sub.2                                                         (EX. 114)                                                                128  l-17,20-tetranor-                                                                        Butanethiol                                                                             B    l-11-deoxy-11α-butylthio-17,20-tetra-         16-m-trifluoro-           nor-16-m-trifluoromethylphenoxy-                    methylphenoxy-            prostaglandin-E.sub.2                               prostaglandin-A.sub.2                                                         (EX. 107)                                                                129  l-17,20-tetranor-                                                                        Methanethiol                                                                            B    l-11-deoxy-11α-methylthio-17,20-              16-m-chloro-              tetranor-16-m-chlorophenoxy-                        phenoxyprosta-            prostaglandin-E.sub.2                               glandin-A.sub.2                                                               (EX. 104)                                                                __________________________________________________________________________

EXAMPLES 130-140

Treatment of the following prostaglandins A₁, listed in the table below,with the following indicated oganic lithium cuprate reagents in themanner of Examples 18 or 19 as indicated is productive of the 11-alkyl,or 11-alkenyl prostaglandin E type.

    __________________________________________________________________________    Ex- Starting   Cuprate       Product                                          ample                                                                             Prostaglandin A                                                                          Reagent Method                                                                              11-Substituted-11-deoxyprostaglandin             __________________________________________________________________________                                 E                                                130 l-prostaglandin-A.sub.3                                                                  dimethyl copper                                                                       18    l-11-deoxy-11α-methylprostaglandin-E.su                                 b.3                                                  (Example 109)                                                                            lithium                                                        131 l-prostaglandin-A.sub.2                                                                  dimethyl copper                                                                       18    l-11-deoxy-11α-methylprostaglandin-E.su                                 b.2                                                  methyl ester                                                                             lithium       methyl ester                                     132 l-15-epiprosta-                                                                          diethyl copper                                                                        18    l-11-deoxy-11α-ethyl-15-epi-prosta-            glandin-A.sub.2                                                                          lithium       glandin-E.sub.2                                  133 l-prostaglandin-A.sub.2                                                                  diphenylcopper                                                                        19    dl-11-deoxy-11α-phenylprostaglandin                                     E.sub.2                                              methyl ester                                                                             lithium       and dl-11-deoxy-11β-phenylprostaglandin-                                 E.sub.2 methyl ester                             134 l-15-methylprosta-                                                                       dimethyl copper                                                                       19    l-deoxy-11α-methyl-15-methylprostagland                                 in-                                                  glandin-A.sub.2                                                                          lithium       E.sub.2 methyl ester                                 methyl ester                                                              135 l-16,16-dimethyl-                                                                        dimethyl copper                                                                       18    l-11-deoxy-11α-methyl-16,16-dimethyl-          prostaglandin-A.sub.1                                                                    lithium       prostaglandin-E.sub.1 methyl ester                   methyl ester                                                              136 l-16(S)-methyl-                                                                          divinylcopper                                                                         19    l-11-deoxy-11α-vinyl-16(S)-methylprosta                                 -                                                    prostaglandin-A.sub.2                                                                    lithium       glandin-E.sub.2                                  137 l-16-fluoroprosta-                                                                       di(1-butenyl)-                                                                        19    l-11-deoxy-11α-(1-butentyl)-16-fluoro-         glandin-A.sub.1                                                                          copper lithium                                                                              prostaglandin-E.sub.2                            __________________________________________________________________________    Ex- Starting   Cuprate Method                                                                              Product                                          ample                                                                             Prostaglandin                                                                            Reagent of Example                                                                          11-Substituted-11-deoxyprostaglandin-E           __________________________________________________________________________    138 l-20-ethylprosta-                                                                        dipropentyl-                                                                          19    1-11-deoxy-11α-propenyl-20-ethylprosta-        glandin-A.sub.2 (Ex. 103)                                                                copper lithium                                                                              glandin-E.sub.2                                  139 l-17,20-tetranor-                                                                        dimethyl-                                                                             18    l-11-deoxy-11α-methyl-17,20-tetranor-m-        16-m-trifluoro-                                                                          copper lithium                                                                              trifluoromethylphenylprostaglandin-E.sub.2           phenoxyprostaglan-                                                            din-A.sub.2 (Ex. 114)                                                     140 l-17,20-tetranor-                                                                        dimethyl-                                                                             18    l-11-deoxy-11α-methyl-17,20-tetranor-16                                 -                                                    16-m-chlorophen-                                                                         copper lithium                                                                              m-chlorophenoxyprostaglandin-E.sub.2                 oxyprostaglandin-                                                             A.sub.2 (Ex. 104)                                                         140A                                                                              l-17,20-tetranor-                                                                        divinyl-                                                                              19    l-11-deoxy-11α-vinyl-17,20-tetranor-16-        16-m-trifluoro-                                                                          copper lithium                                                                              m-trifluoromethylphenoxyprostaglandin-               methylphenoxyprosta-     E.sub.2                                              glandin-A.sub.2 (Ex. 114)                                                 140B                                                                              l-17,20-tetranor-16-                                                                     divinyl-                                                                              19    l-11-deoxy-11α-vinyl-17,20-tetranor-16-        m-chlorophenoxy-                                                                         copper lithium                                                                              m-chlorophenoxyprostaglandin-E.sub.2                 prostaglandin-A.sub.2                                                         (Ex. 104)                                                                 140C                                                                              l-17,20-tetranor-16-                                                                     divinyl-                                                                              19    l-11-deoxy-11α-vinyl-17,20-tetranor-16-        p-fluorophenoxy-                                                                         copper lithium                                                                              p-fluorophenoxyprostaglandin-E.sub.2                 prostaglandin-A.sub.2                                                         (Ex. 106)                                                                 140D                                                                              l-16,16-dimethyl-                                                                        divinyl-                                                                              19    l-11-deoxy-11α-vinyl-16,16-dimethyl-           prostaglandin-A.sub.2                                                                    copper lithium                                                                              prostaglandin-E.sub.2                            __________________________________________________________________________

EXAMPLES 141-145

Reduction of the 11-deoxy-11-alkylprostaglandins E listed in the tablebelow by the procedure of Example 29 yields the11-alkyl-11-deoxy-13,14-dihydroprostaglandins-E₁ of the table.

    __________________________________________________________________________    Example                                                                            Starting 11α-alkyl prostaglandin E                                                        Product 13,14-dihydroprostaglandin                     __________________________________________________________________________                           E.sub.1                                                141  l-11-deoxy-11α-methyl-15-methyl-                                                          l-11-deoxy-11α-methyl-13,14-dihydro-15-methyl                           -                                                           prostaglandin-E.sub.2 methyl ester                                                              prostaglandin-E.sub.1 methyl ester                          (EX. 134)                                                                142  l-11-deoxy-11α-ethyl-15-epi-                                                              l-11-deoxy-11α-ethyl-15-epi-13,14-dihydro-            prostaglandin-E.sub.2 (EX. 132)                                                                 prostaglandin-E.sub.1                                  143  l-11-deoxy-11α-methyl-16,16-di-                                                           l-11-deoxy-11αmethyl-13,14-dihydro-16,16-di-          methylprostaglandin-E.sub.1 methyl                                                              methylprostaglandin-E.sub.1 methyl ester                    ester (EX. 135)                                                          144  l-11-deoxy-11α-phenylprostaglandin-                                                       l-11-deoxy-11α-phenyl-13,14-dihydroprostaglan                           din-                                                        E.sub.2 methyl ester (EX. 133)                                                                  E.sub.1 methyl ester                                   145  l-11-deoxy-11α-methyl-17,20-tetra-                                                        l-11-deoxy-11α-methyl-13,14-dihydro-17,20-tet                           ra-                                                         nor-16-m-trifluoromethylphenoxy-                                                                nor-16-m-trifluoromethylphenoxyprostaglandin-E.sub.                           1                                                           prostaglandin-E.sub.2 (EX. 139)                                          __________________________________________________________________________

EXAMPLES 146-157

Treatment of the 11-deoxy-11α/β-acetylmercaptoprostaglandin E of thefollowing table by the method of Example 236 is productive of the11-deoxy-11α-mercaptoprostaglandin F of the table.

    __________________________________________________________________________         Starting 11-deoxy-11α/β-                                      Example                                                                            acetylmercaptoprostaglandin E                                                                Product 11-deoxy-11α-mercaptoprostaglandin                              Fα                                                  __________________________________________________________________________    146  223            l-11-deoxy-13,14-dihydro-11α-mercaptoprostagland                        in-                                                                           F.sub.1 α                                           147  224            l-11-deoxy-11α-mercaptoprostaglandin-F.sub.3                            α                                                   148  226            l-11-deoxy-15-epi-11α-mercaptoprostaglandin-F.su                        b.2 α                                               149  227            dl-11-deoxy-11α-mercaptoprostaglandin-F.sub.1                           α                                                   150  228            l-11-deoxy-16,16-dimethyl-11α-mercaptoprostaglan                        din-                                                                          F.sub.1 α                                           151  229            l-11-deoxy-16,16-dimethyl-11α-mercaptoprostaglan                        din-                                                                          F.sub.2 α                                           152  230            l-11-deoxy-16(S)-methyl-11α-mercaptoprostaglandi                        n-F.sub.2 α                                         153  231            l-11-deoxy-16-fluoro-11α-mercaptoprostaglandin-F                        .sub.2 α                                            154  232            l-11-deoxy-20-methyl-11α-mercaptoprostaglandin-F                        .sub.2 α                                            155  233            dl-11-deoxy-17,20-tetranor-11α-mercapto-16-m-tri                        -                                                                             fluoromethylphenoxyprostaglandin-F.sub.2 α          156  234            l-11-deoxy-16-p-fluorophenoxy-17,20-tetranor-11α                        -                                                                             mercaptoprostaglandin-F.sub.2 α                     157  235            l-16-m-chlorophenoxy-11-deoxy-17,20-tetranor-11α                        -                                                                             mercaptoprostaglandin-F.sub.2 α                     __________________________________________________________________________

EXAMPLES 158-167

Treatment of the following A type prostaglandins by the procedure ofExample 68 is productive of the 11α and 11β-cyano prostaglandins of thetable. The 11α and 11β-epimers are separable from each other bychromatographic procedures (see Example 212).

    __________________________________________________________________________    Example                                                                            Starting Prostaglandin A                                                                       Product 11α/β-cyano-11-deoxyprostaglandin                           E                                                      __________________________________________________________________________    158  l-prostaglandin-A.sub.3 (EX. 109)                                                              l-11-deoxy-11α-cyanoprostaglandin-E.sub.3                               and                                                                           l-11-deoxy-11β-cyanoprostaglandin-E.sub.3          159  dl-prostaglandin-A.sub.2                                                                       dl-11-deoxy-11α-cyanoprostaglandin-E.sub.2                              and                                                                           dl-11-deoxy-11β-cyanoprostaglandin-E.sub.2         160  l-15-methylprostaglandin-A.sub.2                                                               l-11-deoxy-11α-cyano-15-methylprostaglandin-E.                          sub.2                                                        methyl ester     and l-11-deoxy-11β-cyano-15-methylprosta-                                glandin-E.sub.2 methyl esters                           161  l-16,16-dimethylprostaglandin-A.sub.2                                                          l-11-deoxy-11α-cyano-16,16-dimethylprosta-                              glandin-E.sub.2 and l-11-deoxy-11β-cyano-16,16-                          di-                                                                           methylprostaglandin-E.sub.2                             162  l-16(S)-methylprostaglandin-A.sub.2                                                            l-11-deoxy-11α-cyano-16(S)-methylprostaglandin                          -                                                                             E.sub.2 and l-11-deoxy-11β-cyano-16(S)-methyl-                           prostaglandin-E.sub.2                                   163  l-16,16-difluoroprostaglandin-A.sub.2                                                          l-11-deoxy-11α-cyano-16,16-difluoroprostagland                          in-                                                                           E.sub.2 and l-11-deoxy-11β-cyano-16,16-difluoro                          -                                                                             prostaglandin-E.sub.2                                   164  l-16-fluoroprostaglandin-A.sub.2                                                               l-11-deoxy-11α-cyano-16-fluoroprostaglandin-E.                          sub.2                                                                         and d-11-deoxy-11β-cyano-16-fluoroprosta-                                glandin-E.sub.2                                         165  dl-17,20-tetranor-16-p-fluoro-                                                                 dl-11-deoxy-11α-cyano-17,20-tetranor-16-p-fluo                          ro-                                                          phenoxyprostaglandin-A.sub.2                                                                   phenoxyprostaglandin-E.sub.2 and dl-11-deoxy-11.beta                          .-                                                           methyl ester (EX. 113)                                                                         cyano-17,20-tetranor-16-p-fluorophenoxyprosta-                                glandin-E.sub.2                                         166  l-17,20-tetranor-16-m-trifluoro-                                                               l-11-deoxy-11α-cyano-17,20-tetranor-16-m-tri-          methylphenoxyprostaglandin-A.sub.2                                                             fluoromethylphenoxyprostaglandin-E.sub.2 and l-11-           (EX. 107)        deoxy-11β-cyano-17,20-tetranor-16-m-trifluoro-                           methylphenoxyprostaglandin-E.sub.2                      167  l-17,20-tetranor-16-m-chloro-                                                                  l-11-deoxy-11α-cyano-17,20-tetrano-16-m-chloro                          -                                                            phenoxyprostaglandin-A.sub.  2                                                                 phenoxyprostaglandin-E.sub.2 and l-11-deoxy-11β                          -                                                            (EX. 104)        cyano-17,20-tetranor-16-m-chlorophenoxyprosta-                                glandin-E.sub.2                                         __________________________________________________________________________

EXAMPLE 168 Preparation of 11-deoxy-11α-hydroxymethyl-15-O-acetylprostaglandin-E₂ methyl ester, 11-deoxy-11β-hydroxymethyl-15-O-acetylprostaglandin-E₂ methyl ester, and8-iso-11-deoxy-11α-hydroxymethyl-15-O-acetyl prostaglandin-E₂ methylester

A solution of 30 gm. (77 mmol) of 15-O-acetylprostaglandin-A₂ methylester benzophenone in 4 l. of methanol is irradiated with a Hanovia 450medium pressure lamp thru a pyrex immersion well for 5 hours at ambienttemperature. The solvent is removed in vacuo and the residue istriturated 10 times with 100 ml. of petroleum ether (30°-60° C.). Theinsoluble material (35 gm.) is chromatographed on a 4 foot ×6 inch (flatdiaeter) nylon column of acid washed silica gel using ethylacetate/benzene (1:3). The column is developed several times andfractions are collected.

From the chromatography is obtained 6 gm. of11-deoxy-11β-hydroxymethyl-15-O-acetylprostaglandin-E₂ methyl ester:νmax 3400, 1735 cm⁻¹ ; [α]_(D) ²⁵ =-86°. (c=0.2, MeOH); CDΔε=-3.2 at 293nm. There is obtained both 8-iso and8-normal-11-deoxy-11α-hydroxymethyl-15-O-acetylprostaglandin-E₂ methylester. These two products are further purified by dry columnchromatography to give pure11-deoxy-11α-hydroxymethyl-15-O-acetylprostaglandin-E₂ methyl ester:νmax-2.8 3400, 1735 cm⁻¹, [α]_(D) ²⁵ =-40°. (c=0.2, MeOH), CD:Δε=-at 293nm; and pure 8-iso-11-deoxy-15-O-acetylprostaglandin-E₂ methyl ester:νmax 3400, 1735 cm⁻¹ ; [α]_(D) ²⁵ =+25° (c=0.2, MeOH); CD:Δε=+2.04 at293 nm.

EXAMPLES 169-182

Treatment of the following A type prostaglandins with the indicatedalcohols in the manner of Example 168 gives the products of the table.

    __________________________________________________________________________    Example                                                                            Starting Prostaglandin                                                                     Alcohol                                                                              Product                                              __________________________________________________________________________    169  l-13-dihydroprostaglandin-                                                                 Ethanol                                                                              l-11-deoxy-11α-(1-hydroxyethyl)-13-dihydro-                             N                                                         A.sub.1             prostaglandin-E.sub.1 and 11-deoxy-11α-(1-h                             ydroxy-                                                                       ethyl)-13-dihydroprostaglandin-E.sub.1 and                                    8-iso-                                                                        11-deoxy-11α-(1-hydroxyethyl)-13-dihydro-                               prostaglandin-E.sub.1                                170  l-prostaglandin-A.sub.1                                                                    Isopropanol                                                                          l-11-deoxy-11α-(1-hydroxy-1-methylethyl)-                               prostaglandin-E.sub.1                                171  l-prostaglandin-A.sub.3                                                                    Methanol                                                                             l-11-deoxy-11α-hydroxymethyl-prostaglandin-                             E.sub.3                                                   (EX. 109)           and l-11-deoxy-11α-hydroxymethylprostagland                             in-                                                                           E.sub.3 and 8-iso-11-deoxy-11α-hydroxymethy                             lprosta-                                                                      glandin-E.sub.3                                      172  l-15-epiprostaglandin-A.sub.2                                                              Methanol                                                                             l-11-deoxy-11α-hydroxymethyl-15-epiprosta-                              glandin-E.sub.2 and l-11-deoxy-11α-hydroxym                             ethyl-15-                                                                     epiprostaglandin E.sub.2 and 8-iso-11-deoxy-11-                               hydroxymethyl-15-epiprostaglandin-E.sub.2            173  l-15-O-acetylprosta-                                                                       Isopropanol                                                                          l-11-deoxy-11α-(1-hydroxy-1-methylethyl)-15                             -O-                                                       glandin-A.sub.2 methyl ester                                                                      acetylprostaglandin-E.sub.2 methyl ester             174  dl-prostaglandin-A.sub.2                                                                   methanol                                                                             dl-11-deoxy-llα-hydroxymethylprostaglandin-                             E.sub.2                                                                       dl-11-deoxy-11β-hydroxymethylprostaglandin-E                             .sub.2                                                                        and dl-8-iso-11α-hydroxymethylprostaglandin                             -E.sub.2                                             175  l-15-methylprostaglandin-                                                                  Methanol                                                                             l-11-deoxy-11α-hydroxymethyl-15-methylprost                             a-                                                        A.sub.2 methyl ester                                                                              glandin-E.sub.2 methyl ester; l-11-deoxy-11β                             -hydroxy-                                                                     methyl-15-methylprostaglandin-E.sub.2 and                                     8-iso-                                                                        11-deoxy-11α-hydroxymethyl-15-methylprosta-                             glandins-E.sub.2 methyl ester                        176  l-16,16-dimethylprosta-                                                                    Methanol                                                                             l-11-deoxy-11α-(1-hydroxymethyl)-16,16-dime                             thyl-                                                     glandin-A.sub.1     prostaglandin-E.sub.1 ; l-11-deoxy-11β-(1-hy                             droxy-                                                                        methyl)-16,16-dimethylprostaglandin-E.sub.1 and                               8-iso-11-deoxy-11α-(hydroxymethyl)-16,16-di                             -                                                                             methylprostaglandin-E.sub.1                          177  l-16(R)-methylprosta-                                                                      Methanol                                                                             l-11-deoxy-11α-hydroxymethyl-16(R)-methylpr                             osta-                                                     glandin-A.sub.2     glandin-E.sub.2 ; l-11-deoxy-llβ-hydroxymeth                             yl-16(R)-                                                                     methylprostaglandin-E.sub.2 and                                               8-iso-11-deoxy-11α-                                                     hydroxymethyl-16(R)-methylprostaglandin-E.sub.2      178  l-16,16-difluoroprosta-                                                                    Methanol                                                                             l-11-deoxy-11α-hydroxymethyl-16,16-difluoro                             -                                                         glandin-A.sub.2     prostaglandin-E.sub.2 ; l-11-deoxy-11β-hydro                             xymethyl-                                                                     16,16-difluoroprostaglandin-E.sub.2 and                                       8-iso-11-                                                                     deoxy-11α-hydroxymethyl-16,16-difluoroprost                             a-                                                                            glandin-E.sub.2                                      179  l-20-ethylprostaglandin-                                                                   Methanol                                                                             l-11-deoxy-11α-hydroxymethyl-20-ethyl-              A.sub.2             prostaglandin-E.sub.2 ; l-11-deoxy-11β-hydro                             xy-                                                                           methyl-20-ethylprostaglandin-E.sub.2 and 8-iso-                               11-deoxy-11α-hydroxymethyl-20-ethyl-                                    prostaglandin-E.sub.2                                180  dl-17,20-tetranor-16-m-                                                                    Methanol                                                                             dl-11-deoxy-11α-hydroxymethyl-17,20-tetra-          trifluoromethylphenoxy-                                                                           nor-16-m-trifluoromethylphenoxyprosta-                    prostaglandin-A.sub.2                                                                             glandin-E.sub.2 ; dl-11-deoxy-11β-hydroxymet                             hyl-                                                      (Example 114)       17,20-tetranor-16-m-trifluoromethylphenoxy-                                   prostaglandin-E.sub.2 and dl-8-iso-11-deoxy-11.al                             pha.-                                                                         hydroxymethyl-17,20-tetranor-16-m-trifluoro-                                  methylprostaglandin-E.sub.2                          181  l-17,20-tetranor-16-p-                                                                     Isopropanol                                                                          l-11-deoxy-11α-(1-hydroxy-1-methylethyl)-           fluorophenoxyprosta-                                                                              17,20-tetranor-16-p-fluorophenoxyprosta-                  glandin-A.sub.2 (Example 113)                                                                     glandin-E.sub.2                                      182  l-17,20-tetranor-16-m-                                                                     Methanol                                                                             l-11-deoxy-11α-hydroxymethyl-17,20-tetranor                             -                                                         chlorophenoxyprosta-                                                                              16-m-chlorophenoxyprostaglandin-E.sub.2 ; l-11-           glandin-A.sub.2 (Example 111)                                                                     11β-hydroxymethyl-17,20-tetranor-16-m-                                   chlorophenoxyprostaglandin-E.sub.2 and l-8-iso-                               11-deoxy-11α-hydroxymethyl-17,20-tetranor-                              S                                                                             16-m-chlorophenoxyprostaglandin-E.sub.2              __________________________________________________________________________

EXAMPLE 183 Preparation of 11-deoxy-11β-hydroxymethyl-prostaglandin E₂

To a solution of 395 mg. (0.94 mmol) of11-deoxy-11β-hydroxymethyl-15-O-acetyl prostaglandin E₂ methyl ester(Example 168) in 2 ml. of methanol is added 1.6 ml. of a 2.5 N aqueoussodium hydroxide solution. The solution is stirred at ambienttemperature for 1.5 hour and is then diluted with 20 ml. of water,saturated with sodium chloride, acidified with 6 N aqueoushydrochloricacid and extracted twice with 50 ml. of ether. The ethersolutions are combined, dried with anhydrous magnesium sulfate andconcentrated in vacuo to give 320 mg. of11-deoxy-11β-hydroxymethylprostaglandin-E₂ ; νmax 3400-2700 cm⁻¹, 1735cm⁻¹ ; [α]_(D) ²⁵ =-59.3° (C=0.43 MeOH); CD: ΔE=-3.2.

EXAMPLE 184 Preparation of 11-deoxy-11α-hydroxymethyl-prostaglandin-E₂and 8-iso-11-deoxy-11α-hydroxymethyl-prostaglandin-E₂

To a solution of 810 mg. of 11-deoxy-11α-hydroxymethyl-15-O-acetylprostaglandin methyl ester (Example 168) in 5 ml. of methanol is added2.5 ml. of 2.5 N aqueous sodium hydroxide solution. The solution isstirred at room temperature for 2.5 hours and is then diluted with 25ml. of water, saturated with sodium chloride, acidified with 1.1 ml. 6 Naqueous hydrochloric acid and extracted twice with 20 ml. of ether. Theetheral solutions are combined, dried with anhydrous magnesium sulfateand concentrated in vacuo to give 680 mg. of a mixture of 8-normal and8-iso-11α-hydroxymethyl-15-O-acetyl prostaglandin E₂. The mixture of8-isomers is chromatographed on a 48"×15/8" flat diameter dry column ofacid washed silica gel using ethyl acetate/benzene/acetic acid (3:2:2%).The column was developed 3 times and then cored at each 0.1 Rf unit todetermine the position of each isomer. Rf fractions 0.1-0.25 and0.35-0.7 were washed with ether to give 11-deoxy-11α-hydroxymethylprostaglandin E₂ : νmax 3400, 1720-1690, 975 cm⁻¹ ; [α]_(D) ²⁵ =-6°(c=0.21, MeOH); CD:Δε=-2.5 at 293 nm and8-iso-11-deoxy-11α-hydroxymethyl prostaglandin-E₂ : νmax 3400,1720-1690, 975 cm⁻¹ ; [α]_(D) ²⁵ =+37° (c=0.23, MeOH); CD:Δε=+2.04 at293 nm, respectively.

EXAMPLE 184A Preparation of11-deoxy-11α-(1-hydroxy-1-methylethyl)prostaglandin-E₂

The subject compound is prepared from the corresponding 15-O-acetylmethyl ester (Example 173) by saponification according to the methoddescribed in Example 183 above.

EXAMPLE 185 Preparation of11-deoxy-11α-(1,3-dioxolan-2-yl)-15-O-acetylprostaglandin-E₂ methylester and 11-deoxy-11α-(1,3-dioxolan-2-yl)-15-O-acetylprostaglandin-E₂methyl ester

A solution of 5.0 gm. of 1-15-O-acetylprostaglandin-A₂ methyl ester and1.2 gm. of benzophenone in 300 ml. of undistilled 1,3-dioxolan isirradiated with a medium pressure Hanovia U.V. Lamp through a Pyrexfilter. After 20 minutes tlc indicates the reaction is complete. Thesolvent is removed in vacuo to afford 8 gm. of an oil.

The material is purified by partition chromatography usingheptane-acetonitrile to give: 4.4 gm of1-11-deoxy-11α-(1,3-dioxolan-2-yl)-15-O-acetprostaglandin-E₂ methylester (low Rf material) and 1.72 gm of1-11-deoxy-11α-(1,3-dioxolan-2-yl)-15-O-acetylprostaglandin-E₂ methylester (high Rf material) (tlc system 20% ethylacetate in benzene, silicagel, 2x).

The above products have nearly identical IR spectra 3400 cm⁻¹ ;1740-1720 cm⁻¹, 975 cm⁻¹, [α]_(D) ²⁵ of high Rf material=-19° (c=0.42MeOH), [α]_(D) ²⁵ of low Rf material=-81° (c=0.36 MeOH), CD of high Rf:294=-3.30 CD of low Rf:-3.72.

The configuration of the 1,3-dioxolano-2-yl function is assigned to eachcompound on the basis of the products derived from saponification ofeach diester. The high Rf material, upon saponification (see Example184) gives two products which are assigned1-11-deoxy-11α-(1,3-dioxolan-2-yl)-PGE₂ and8-iso-11-deoxy-11α-(1,3-dioxolan-2-yl)-PGE₂. The low Rf diester uponidentical saponfication conditions gave only a single isomer:1-11-deoxy-11α-(1,3-dioxolan-2-yl)-PGE₂. Since it is very unlikely thata derivative with the 11α-configuration would give an 8-iso compound,the high Rf diester is assigned 11α.

EXAMPLES 186-198

Treatment of the following A type prostaglandins with the following inthe manner of Example 185 is productive of the11-(1,3-dioxolanyl-prostaglandins-E of the table.

    __________________________________________________________________________    Example                                                                            Starting Prostaglandin                                                                            Product                                              __________________________________________________________________________    186  l-13-dihydroprosta-                                                                        1,3-dioxolan                                                                         l-11-deoxy-11β-(1,3-dioxolan-2-yl)-13-               glandin-A.sub.1     dihydroprostaglandin-E.sub.1 and 11-deoxy-                                    11α-(1,3-dioxolan-2-yl)-13-dihydro-                                     prostaglandin-E.sub.1                                187  l-prostaglandin-A.sub.1                                                                    2-methyl-1,3-                                                                        l-11-deoxy-11α-(2-methyl-1,3-dioxolan-                           dioxolan                                                                             2-yl)-prostaglandin-E.sub.1 and l-11-deoxy-                                   11β-(2-methyl-1,3-dioxolan-2-yl)-                                        prostaglandin-E.sub.1                                188  l-prostaglandin-A.sub.3                                                                    1,3-dioxolan                                                                         l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                 (EX. 109)           prostaglandin-E.sub.3 and l-11-deoxy-11β-                                (1,3-dioxolan-2-yl)-prostaglandin-E.sub.3            189  l-15-epiprostaglandin-                                                                     1,3-dioxolan                                                                         l-11-deoxy-11α-(1,3-dioxolan-2-yl)-15-              A.sub.2             epi-prostaglandin-E.sub.2 and l-11-deoxy-                                     11β-(1,3-dioxolan-2-yl)-15-epi-prosta-                                   glandin-E.sub.2                                      190  dl-prostaglandin-A.sub.2                                                                   1,3-dioxolan                                                                         dl-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                    prostaglandin-E.sub.2 and dl-11-deoxy-11β-                               (1,3-dioxolan-2-yl)-prostaglandin-E.sub.2            191  l-15-methylprosta-                                                                         1,3-dioxolan                                                                         l-11-deoxy-11α-(1,3-dioxolan-2-yl)-15-              glandin-A.sub.1 methyl                                                                            methylprostaglandin-E.sub.1 methyl ester                  ester               and l-11-deoxy-11β-(1,3-dioxolan-2-yl)-                                  15-methylprostaglandin-E.sub.1 methyl ester          192  l-16,16-dimethylprosta-                                                                    2-methyl-1,3-                                                                        l-11-deoxy-11α-(2-methyl-1,3-dioxolan-              glandin-A.sub.2                                                                            dioxolan                                                                             2-yl)-16,16-dimethylprostaglandin-E.sub.2                                     and l-11-deoxy-11β-(2-methyl-1,3-                                        dioxolan-2-yl)-16,16-dimethylprosta-                                          glandin-E.sub.2                                      193  l-16(R)-methylprosta-                                                                      1,3-dioxolan                                                                         l-11-deoxy-11α-(1,3-dioxolan-2-yl)-16(R)-           glandin-A.sub.2     methylprostaglandin-E.sub.2 and l-11-deoxy-                                   11β-(1,3-dioxolan-2-yl)-16(R)-methyl-                                    prostaglandin-E.sub.2                                194  l-16,16-difluoro-                                                                          1,3-dioxolan                                                                         l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                 prostaglandin-A.sub.2                                                                             16,16-difluoroprostaglandin-E.sub.2 and l-11-                                 deoxy-11β-(1,3-dioxolan-2-yl)-16,16-                                     difluoroprostaglandin-E.sub.2                        195  l-20-ethylprosta-                                                                          1,3-dioxolan                                                                         l-11-deoxy-11α-(1,3-dioxolan-2-yl)-20-              glandin-A.sub.2     ethylprostaglandin-E.sub.2 and l-11-deoxy-                                    11β-(1,3-dioxolan-2-yl)-20-ethyl-                                        prostaglandin-E.sub.2                                196  dl-17,20-tetranor-                                                                         1,3-dioxolan                                                                         dl-11-deoxy-11α-(1,3-dioxolan-2-yl)-17,             16-m-trifluoro-     20-tetranor-16-m-trifluoromethyl-                         phenoxyprostaglandin-                                                                             phenoxyprostaglandin-E.sub.2 and dl-11-deoxy-             A.sub.2 (Example 114)                                                                             (1,3-dioxolan-2-yl)-17,20-tetranor-16-                                        m-trifluoromethylphenoxyprostaglandin-E.sub.2        197  l-17,20-tetranor-16-                                                                       1,3-dioxolan                                                                         l-11-deoxy-11α-(1,3-dioxolan-2-yl)-17,              p-fluorophenoxy-    20-tetranor-16-p-fluorophenoxyprosta-                     prostaglandin-A.sub.2                                                                             glandin-E.sub.2 and l-11-deoxy-11β-(1,3-             (Example 113)       dioxolan-2-yl)-17,20-tetranor-16-p-                                           fluorophenoxyprostaglandin-E.sub.2                   198  l-17,20-tetranor-16-                                                                       1,3-dioxolan                                                                         l-11-deoxy-11α-(1,3-dioxolan-2-yl)-17,              m-chlorophenoxy-    20-tetranor-16-m-chlorophenoxyprosta-                     prostaglandin-A.sub.2                                                                             glandin-E.sub.2 and l-11-deoxy-11β-(1,3-             (Example 111)       dioxolan-2-yl)-17,20-tetranor-16-m-                                           chloroprostaglandin-E.sub.2                          __________________________________________________________________________

EXAMPLE 199 Preparation of a mixture of the methyl esters of11-deoxy-11α-(1-hydroxy-1-methylethyl-15-O-acetyl prostaglandin F₂ B andF₂ β and their separation

To a cold solution of 816 mg. of 11-deoxy-11α-(1-hydroxy-1-methylethyl)-15-O-acetylprostaglandin methyl ester (Example 173) in 10 ml. ofethanol is added to a solution of 280 mg. of sodium borohydride in 15ml. of methanol. After 10 minutes the solution is poured into 100 ml. ofsaturated ammonium chloride and extracted three times with 50 ml. ofether. The ether is combined, dried with magnesium sulfate, andconcentrated in vacuo to give 990 mg. of a yellow oil. The mixture ofthe alcohols (900 mg.) is chromatographed on a 35"×11/2 flat diameterdry column of acid washed silica using ethyl acetate/benzene (2:3). Thecolumn is cored at each 0.1 Rf unit. The following portions are removed:0.75-1.0 and 0.2-0.5. Elution of the 0.75-1.0 portion with 20% methanolin chloroform gave 513 mg. of11-deoxy-11α-(1-hydroxy-1-methylethyl)-15-O-acetyl prostaglandin F₂ αmethyl ester as an oil; νmax 3400, 1720 cm⁻¹ ; nmr (CDCl₃ δ:4.2 (m, 1H,H-9β); [α]²⁵ =-19°; (c=0.21, MeOH). Similar elution of the 0.2-0.5portion gave 270 mg. of11-deoxy-11α-(1-hydroxy-1-methylethyl-15-O-acetyl prostaglandin F₂ α/βmethyl ester; νmax: 3400, 1720 cm⁻¹ pmr (CDCl3) δ:3.9 (m, 1H, H-9β)[α]_(D) ²⁵ =-26° (0.22, MeOH).

EXAMPLES 200-211

Treatment of the following E type prostaglandins with sodium borohydridein ethanol by the procedure of Example 199 provides the mixture of9-hydroxy prostanoic acids or esters of the following table. The F.sub.αand F.sub.β components are separable by chromatography.

    __________________________________________________________________________    Example                                                                            Starting E Prostaglandin                                                                          Product F Prostaglandins                             __________________________________________________________________________    200  l-11-deoxy-11α-ethylthioprosta-                                                            l-11-deoxy-11α-ethylthioprostaglandins-              glandin-E.sub.3 (EX. 115)                                                                        F.sub.3 α and F.sub.3 β                    201  l-11-deoxy-11α-ethylthio-16-p-                                                             l-11-deoxy-11α-ethylthio-16-p-fluorophenoxy-                            N                                                          fluorophenoxyprostaglandin-E.sub.2                                                               prostaglandins-F.sub.2 α and F.sub.2                                    β                                                     (EX. 126)                                                                202  l-11-deoxy-11α-vinyl-16(S)-methyl-                                                         l-11-deoxy-11α-vinyl-16(S)-methylprosta-             prostaglandin-E.sub.2 (EX. 136)                                                                  glandins-F.sub.2 α and F.sub.2 β           203  l-11-deoxy-11α-methyl-13,14-di-                                                            l-11-deoxy-11α-methyl-13,14-dihydro-17,20-           hydro-17,20-tetranor-16-m-tri-                                                                   tetranor-16-m-trifluoromethylphenoxy-                      fluoromethylphenoxyprostaglandin-                                                                prostaglandins-F.sub.1 α and F.sub.1                                    β                                                     E.sub.1 (EX. 145)                                                        204  l-11-deoxy-11α-methyl-16,16-di-                                                            l-11-deoxy-11α-methyl-16,16-dimethylprosta-                             O                                                          methyl prostaglandin-E.sub.2 (EX. 135)                                                           glandins-F.sub.2 α and F.sub.2 β           205  l-11-deoxy-11α-methyl-17,20-                                                               l-11-deoxy-11α-methyl-17,20-tetranor-16-             tetranor-16-m-chlorophenoxy-                                                                     m-chlorophenoxyprostaglandins F.sub.2 α and                             F.sub.2 β                                             prostaglandin-E.sub.2 (EX. 140)                                          206  dl-11-deoxy-11α-cyano-17,20-tetra-                                                         dl-11-deoxy-11α-cyano-17,20-tetranor-16-p-           nor-16-p-fluorophenoxyprosta-                                                                    fluorophenoxyprostaglandins-F.sub.2 α and                               F.sub.2 β                                             glandin-E.sub.2 (Ex. 165)                                                207  l-11-deoxy-11α-hydroxymethyl-                                                              l-11-deoxy-11α-hydroxymethylprostaglandin-           prostaglandin-E.sub.2 (EX. 184)                                                                  F.sub.2 β                                        208  l-11-deoxy-11β-hydroxymethyl-                                                               l-11-deoxy-11β-hydroxymethyl-15-epiprosta-            15-epiprostaglandin-E.sub.2                                                                      glandins-F.sub.2 α and F.sub.2 β                (EX. 172)                                                                209  8-iso-11-deoxy-11α-hydroxy-                                                                8-iso-11-deoxy-11α-hydroxymethyl-16(R)-              methyl-16(R)-methylprosta-                                                                       methylprostaglandins-F.sub.2 α and F.sub.2                              β                                                     glandin-E.sub.2 (EX. 177)                                                210  l-11-deoxy-11β-(1,3-dioxolan-                                                               l-11-deoxy-11β-(1,3-dioxolan-2-yl)-prosta-            2-yl)-prostaglandin-E.sub.2 (EX. 185)                                                            glandins-F.sub.2 α and F.sub.2 β           211  l-11-deoxy-11α1,3-dioxolan-                                                                l-11-deoxy-11α-(1,3-dioxolano-2-yl)-17,20-           2-yl)-17,20-tetranor-16-p-fluoro-                                                                tetranor-16-p-fluorophenoxyprostaglandins-                 fluorophenoxyprostaglandin-                                                                      F.sub.2 α and F.sub.2 β                         E.sub.2 (EX. 197)                                                        __________________________________________________________________________

EXAMPLE 212 Separation of 1-11-deoxy-11α-cyanoprostaglandin E₂ and1-11-deoxy-11α-cyanoprostaglandin-E₂ by silica gel chromatography

A solution of 2.6 gm. of a mixture of1-11-deoxy-11α-cyanoprostaglandins-E₂ and11-deoxy-11β-cyanoprostaglandin-E₂ (Example 71) in 5 ml. of methylenechloride was placed on top of a 40"×2" flat diameter nylon column placedwith acid washed silica. The column was developed with 40% ethylacetatein benzene containing 2% acetic acid. A single development required 700ml. A total of 1700 ml. was used with 100 ml. fractions being collected.Fraction 6 contained 540 mg. of pure1-11-deoxy-11α-cyanoprostaglandin-E₂ [α]_(D) ²⁵ =0° (C=0.65 MeOH) λmax.3400, 1730-1690; 975 cm⁻¹ ; pmr CDCl₃ (δ): 3.2-3.5 (m, 1H, H-11),4.2-4.3 (m, 1H, H₁₅), 5.2-5.5 (m, 2H, H5, H6), 5.7-5.85 (m, 2H, H13,H14), Δε296=-2.46. Fraction 4 consisted of primarily1-11-deoxy-11β-cyanoprostaglandin-E₂ [α]_(D) ²⁵ =35° (C=0.67 MeOH) λmax.3400, 1730-1710, 975 cm⁻¹ ; pmr CDCl₃ (δ): 4.2 (m, 1H, H15), 5.3-5.6 (m,2H, H5, H6), 5.6-6.0 (mM, 2H, H13, H14), Δε296=-0.26.

EXAMPLES 213-216

Treatment of the following E type prostanoic acids with lithiumtri-sec-butyl borohydride in tetrahydrofuran by the method of Example 81furnishes the 9-hydroxy prostanoic acids of the following wherein the9-hydroxy group is cis to the 11-substituent.

    __________________________________________________________________________    Example                                                                            Starting 9-oxo prostaglandin                                                                    Product 9-hydroxy prostaglandin                        __________________________________________________________________________    213  l-11-deoxy-11β-cyanoprostaglandin-                                                         l-11-deoxy-11β-cyanoprostaglandin-F.sub.2                                β                                                      E.sub.2 (EX. 212)                                                        214  l-11-deoxy-11α-phenylprostaglandin-                                                       l-11-deoxy-11α-phenylprostaglandin-F.sub.2                              α                                                     E.sub.2 (EX. 133)                                                        215  l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                       l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                   prostaglandin-E.sub.2 (EX. 188)                                                                 prostaglandin-F.sub.2 α                          216  dl-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                      dl-11-deoxy-11α-(1,3-dioxolan-2-yl)-17,               17,20-tetranor-16-p-fluoro-                                                                     20-tetranor-16-p-fluoroprostaglandin-F.sub.2                                  α                                                     prostaglandin-E.sub.2 (EX. 211)                                          __________________________________________________________________________

EXAMPLE 217 Preparation of1-11-deoxy-11α-formyl-15-O-acetylprostaglandin-E₂ methyl ester from1-11-deoxy-11α-(1,3-dioxolan-2-yl)-15-O-acetylprostaglandin-E₂ methylester

A solution of 1 gm. of1-11-deoxy-11α-(1,3-dioxolan-2-yl)-15-O-acetylprostaglandin-E₂ methylester (Example 185) in 20 ml. of a solution consisting of acetic acid,tetrahydrofuran and water in a 2:1:1 ratio is heated to 45° C. for 16hours. The cooled solution is concentrated in vacuo and the residue isdiluted with 100 ml. of benzene and washed twice with 100 ml. of brine.The benzene layer is separated and after drying with magnesium sulfateis concentrated in vacuo to give the subject compound: λmax: 1740-1710cm⁻¹, 975 cm⁻¹.

EXAMPLES 218-222

Subjection of the following 11-1,3-dioxolan-2-yl prostaglandins of thetable to the reaction conditions of Example 217 is productive of theproducts listed in the table.

    __________________________________________________________________________    Example                                                                            Starting Prostaglandin                                                                          Product Prostaglandin                                  __________________________________________________________________________    218  l-11-deoxy-11β-(2-methyl-1,3-                                                              l-11-deoxy-11β-acetylprostaglandin-E.sub.1             dioxolan-2-yl)prostaglandin-E.sub.1                                           (EX. 187)                                                                219  l-11-deoxy-11α-(1,3-dioxolan-2-                                                           l-11-deoxy-11α-formyl-15-epi-prosta-                  yl)-15-epi-prostaglandin-E.sub.2                                                                glandin-E.sub.2                                             (Ex. 189)                                                                220  l-11-deoxy-11α-(1,3-dioxolan-2-                                                           l-11-deoxy-11α-formyl-16(R)-methylprosta-             yl)-16(R)-methylprostaglandin-                                                                  glandin-E.sub.2                                             E.sub.2 (EX. 193)                                                        221  l-11-deoxy-11β-(1,3-dioxolan-2-                                                            l-11-deoxy-11β-formyl-16,16-difluoroprosta-            yl)-16,16-difluoroprosta-                                                                       glandin-E.sub.2                                             glandin-E.sub.2 (EX. 194)                                                221A dl-11-deoxy-11α-(1,3-dioxolan-2-                                                          dl-11-deoxy-11α-formyl-17,20-tetranor-16-             yl)-17,20-tetranor-16-m-tri-                                                                    m-trifluoromethylprostaglandin-E.sub.2                      fluoromethylprostaglandin-E.sub.2                                             (Ex. 196)                                                                222  l-11-deoxy-11α-(1,3-dioxolan-2-                                                           l-11-deoxy-11α-formyl-17,20-tetranor-16-              yl)-17,20-tetranor-16-m-chloro-                                                                 m-chlorophenoxyprostaglandin-E.sub.2                        phenoxyprostaglandin-E.sub.2 (EX. 198)                                   222A l-11-deoxy-11β-(1,3-dioxolan-2-                                                            l-11-deoxy-11β-formylprostaglandin E.sub.2             yl)prostaglandin E.sub.2 (EX. 210)                                       222B l-11-deoxy-11β-(1,3-dioxolo-2-                                                             l-11-deoxy-11β-formylprostaglandin-F.sub.2             yl)prostaglandin F.sub.2 (EX. 210)                                       222C l-11-deoxy-11β-(1,3-dioxolan-2-                                                            l-11-deoxy-11β-formylprostaglandin-E.sub.2             yl)prostaglandin E.sub.2 (EX. 185)                                       __________________________________________________________________________

EXAMPLES 223-235

Treatment of the following A type prostaglandins with the indicatedlower alkanoylthiol carboxylic acid in the manner of Example 13 isproductive of the 11-lower alkanoylthioprostaglandins of the table.

    __________________________________________________________________________                        Reagent thiol                                                                         Product 11α/β-11-deoxy-alkanylthio-                                N                                                 Example                                                                            Starting Prostaglandin A                                                                     alkanoic acid                                                                         prostaglandin E                                   __________________________________________________________________________    223  l-13-dihydroprostaglandin-A.sub.1                                                            thiolpropanoic                                                                        l-11-deoxy-11α-propanoylthio-13-                                acid    dihydroprostaglandin-E.sub.1 and 11-                                          -   deoxy-11β-propanoylthiol-13-dihydro-                                 O                                                                             prostaglandin-E.sub.1                             224  l-prostaglandin-A.sub.3                                                                      thiolacetic                                                                           l-11-deoxy-11α-acetylthioprosta-                                acid    glandin-E.sub.3 and l-11-deoxy-11β-acetyl                                -                                                                             thioprostaglandin-E.sub.3                         225  l-prostaglandin-A.sub.2                                                                      thiolacetic                                                                           l-11-deoxy-11α-acetylthioprosta-                 methyl ester   acid    glandin-E.sub.2 methyl ester and l-11-deoxy-                                  11β-acetylthioprostaglandin-E.sub.2                                      methyl ester                                      226  l-15-epiprostaglandin-A.sub.2                                                                thiolacetic                                                                           l-11-deoxy-11α-acetylthio-15-epi-pro-                           acid    staglandin-E.sub.2 and l-11-deoxy-11β-                                   acetylthio-15-epiprostaglandin-E.sub.2            227  dl-prostaglandin-A.sub.1                                                                     thiolacetic                                                                           dl-11-deoxy-11α-acethylthioprosta-                              acid    glandin-E.sub.1 and dl-11-deoxy-11β-acety                                l-                                                                            thiolprostaglandin-E.sub.1                        228  l-16,16-dimethylprosta-                                                                      thiolacetic                                                                           l-11-deoxy-11α-acetylthio-16,16-di-              glandin-A.sub.1                                                                              acid    methylprostaglandin-E.sub.1 and l-11-deoxy-                                   11β-acetylthio-16,16-dimethylprosta-                                     glandin-E.sub.1                                   229  l-16,16-dimethylprosta-                                                                      thiolacetic                                                                           l-11-deoxy-11-60 -acetylthiol-16,16-di-                glandin-A.sub.2                                                                              acid    methylprostaglandin-E.sub.2 and l-11-deoxy-                                   11β-acetylthio-16,16-dimethylprosta-                                     glandin-E.sub.2                                   230  l-16(S)-methylprosta-                                                                        thiolacetic                                                                           l-11-deoxy-11α-acetylthiol-16(S)-                glandin-A.sub.2                                                                              acid    methylprostaglandin-E.sub.2 and l-11-             deoxy-11β -acetylthio-16(S)-methyl-                                                                  prostaglandin-E.sub.2                             231  l-16-fluoroprostaglandin-                                                                    thiolacetic                                                                           l-11-deoxy-11α-acetylthio-16-fluoro-             A.sub.2        acid    prostaglandin-E.sub.2 and l-11-deoxy-11β-                                acetylthio-16-fluoroprostaglandin-E.sub.2         232  l-20-methylprostaglandin-                                                                    thiolacetic                                                                           l-11-deoxy-11α-acetylthio-20-methyl-             A.sub.2        acid    prostaglandin-E.sub.2 and l-11-deoxy-11β-                                acetylthiol-20-methylprostaglandin-                                           E.sub.2                                           233  dl-17,20-tetranor-16-m-                                                                      thiolacetic                                                                           dl-11-deoxy-11α-acetylthio-17,20-                trifluoromethylphenoxy-                                                                      acid    tetranor-16-m-trifluoromethylphenoxy-                  prostaglandin-E.sub.2  prostaglandin-E.sub.2 and dl-11-                       (EX. 114)              deoxy-11β-acetylthiol-17,20-tetranor-                                    16-m-trifluoromethylphenoxyprostaglan-                                        din-E.sub.2                                       234  l-17,20-tetranor-16-p-                                                                       thiolacetic                                                                           l-11-deoxy-11α-acetylthio-17,20-                 fluorophenoxyprosta-                                                                         acid    tetranor-16-p-fluorophenoxyprosta-                     glandin-A.sub.2        glandin-E.sub.2 and l-11-deoxy-11β-acetyl                                -                                                      (EX. 113)              thiol-17,20-tetranor-16-p-fluoro-                                             phenoxyprostaglandin-E.sub.2                      235  l-17,20-tetranor-16-m-                                                                       thiolacetic                                                                           l-11-deoxy-11α-acetylthio-17,20-                 chlorophenoxyprosta-                                                                         acid    tetranor-16-m-chlorophenoxyprosta-                     glandin-A.sub.2        glandin-E.sub.2 and l-11-deoxy-11β-acetyl                                -                                                      (EX. 111)              thiol-17,20-tetranor-16-m-chloro-                                             phenoxyprostaglandin-E.sub.2                      __________________________________________________________________________

EXAMPLE 236 Preparation of l-11-deoxy-11α-mercaptoprostaglandin-F₂ α

A solution of 2.25 gm. of the crude prostaglandin A₂ extract (60% real)from plexaura homomalla in 10 ml. of thiolacetic acid is heated at 60°C. for 3 hours. After cooling, the solution is diluted with 20 ml. ofbenzene and concentrated in vacuo to an oil. Benzene (40 ml.) is addedand removed in vacuo to provide 2.6 gm. of an oil.

The crude oil is purified by partition chromatography using heptanemethanol on celite to provide 1.4 gm. ofl-11α/β-acetylthio-11-deoxyprostaglandin-E₂ as an oil; λmax: 1740, 1720,975 cm⁻¹.

To a -78° C. solution of 15 ml. of 1.0 M lithiumtri-sec-butylborohydride in tetrahydrofuran/pentane (1:1) is added 1.15gm. (2.8 mmol) of l-11α/β-acetylthio-11-deoxyprostaglandin-E₂ in 5 ml.of tetrahydrofuran. After 30 minutes at -78° C., 10 ml. of water isadded and the resulting mixture is stirred in a 30° C. both for 30minutes. The solution is diluted with an additional 30 ml. of water andextracted four times with 50 ml. of ether.

The aqueous solution is acidified to pH 4 with 2.5 ml. of 6 Nhydrochloric acid, saturated with sodium chloride and extracted twicewith 50 ml. of ether and twice with 50 ml. of ethyl acetate. Thecombined organic extracts are dried with magnesium sulfate andconcentration in vacuo to provide 900 mg. of an oil.

The crude oil is purified on Wolem acid-washed silica-gel usingchloroform as solvent to provide 240 mg. ofl-11-deoxy-11α-mercaptoprostaglandin-F₂ α as a was: λmax: 3400, 1700,975 cm⁻¹ ; pmr (CDCl₃): δ(4.1-4.4, m, 2-H, H9_(b) and H₁₅), (5.05-5.25,M, 4H, exchangeable with CD₃ OD), (5.25-5.7, M, 4H, H₅, H₆, H₁₃ andH₁₄); [α]_(D) ²⁵ =+16° (C=0.35 MeOH).

EXAMPLE 237 Preparation of 11α-cyano-11-deoxyprostaglandin F₂ α,11β-cyano-11-deoxyprostaglandin F₂ β and 11β-cyano-11-deoxyprostaglandinF₂ α

To a solution of 2.84 g. of 40 in 15 ml. of tetrahydrofuran at -78° C.is added 14 ml. of a 0.65 M solution of LPBH. After 60 minutes at -78°C. tlc indicated some ketone remaining after warming to roomtemperature, the solvent is removed in vacuo and 10 ml. of methanol, 5ml. of water and 5 ml. of 2.5 N sodium hydroxide are added. After 3hours, 50 ml. of water is added and the solution is extracted with 3×50ml. of ether. The aqueous phase is acidified with 6 N hydrochloric acid,saturated with sodium chloride and extracted with ether. The ether iswashed with brine, dried and evaporated to yield 2.4 g. of an oil thatconsists of 4 spots of tlc (EtOAc-benzene-HOAc: 40:60:1.5, 2x,silica-gel).

The oil is chromatographed on a 30"×11/2" flat diameter silica-gel) drycolumn using EtOAc-benzene-HOAc (60-40:3) as solvent. TLC of plugsindicates pooling the following Rf fractions: 0.45-0.65 (A), 0.65-0.73(B) and 0.73-0.83 (C). The compound is eluted from the silica-gel with20% MeOH/CHCl₃ to give: A: 912 mg., B: 650 mg., and C: 550 mg.

A and B are combined and rechromatographed on a 30"×11/2" flat diameterdry silica-gel column using ETOAc-OH-HOAc (40-60:3). TLC indicatescombining Fr: 0.2-0.41 (A), 0.41-0.48 (B) and 0.48-0.7 (C). Elution fromthe absorbant will give: A': 230 mg., B': 210 mg. and C': 650 mg. TLCindicates A' nearly pure. Recrystallization of A' from ETOAc-hexanegives 130 mg. of 11β-cyano-11-deoxyprostaglandin-F₂ β: m.p. 76°-78° C.;λmax. 3400-2700, 2220, 1710 cm⁻¹ ; pmr (CDCl₃): δ2.98 (q, 1H, W_(1/2)=20 H_(z), H₁₁α), 3.96 (q, 1H, W_(1/2) =20 H_(z), H₁₁ α), 3.96 (q, 1H,W_(1/2) =20 H_(z), H₉ α), 4.17 (q, 1H, W_(1/2) =18 H.sub. z, H₁₅), 5.48(m, 2H, H₅,6), 5.70 (m, 2H, H₁₃,14); [α]_(D) ²⁵ =+68.8° (C+0.93chloroform). N.O.E.²⁰ indicates that H-11 and the beta alkyl chain aretrans.

A portion of the major component (C+C' combined, 790 mg.) is treatedwith a semicarbizide-acetic acid solution to form the semicarbizone ofunreacted ketone that possesses nearly the same Rf as the products. Theresulting oil is chromatographed on a 24"×1" flat diameter drysilica-gel column using EtOAc-benzene-HOAc (20:30:1). Elution of thematerial from Rf 0.35-0.55 with 20% methanol-chloroform give 375 mg. of11α-cyano-11-deoxyprostaglandin F₂ α as an oil that solidifies uponstorage at -10°; λmax 3400-2200, 2220, 1710 cm⁻¹ ; pmr (CDCl₃): δ2.6 (m,˜2H, H₁₁,12), 4.17-4.3 (m, 2H, H₉ β,₁₅), 5.50 (m, 3H, H₅,6,13), 5.76(d-d, 1H, J=15 Hz, Jobs 14,15=5 Hz, H₁₄); [α]_(D) ²⁵ =+2.24°, (C=0.713,chloroform). N.O.E.²⁰ indicates that H- 11 and the beta alkyl chain werecis.

B' is recrystallized to give a solid that is a mixture of11β-cyano-11-deoxyprostaglandin F₂ β and the next less plar component.The pmr spectrum (CDCl₃) indicated this material consists of11β-cyano-11-deoxyprostaglandin F₂β and 11β-cyano-11-deoxyprostaglandinF₂β and (1:1): δ2.96 (two overlapping quartets, H₁₁ α), 3.97 (q, 1/2H, W1/2-20 Hz, H₉α), 4.18 (m, H₁₅ and H₉β, 11/2H), 5.48 (m, H₅,6) and5.65-5.9 (m, H₁₃,14). Compounds are assumed epimeric at C-9 since theirH₁₁ resonances are nearly coincident.

EXAMPLES 238-326

Carbonyl reduction of the listed prostaglandin E derivatives by theprocedure of the example designated will furnish the productprostaglandins F of the following table. In these instances where aprostaglandin Fα and a prostaglandin F.sub.β are formed, thesecomponents are separable by chromatographic procedures (see Example 237for an illustrative example).

    __________________________________________________________________________         Starting 11-Substituted                                                                        Method                                                                              Product 11-Substituted                            Example                                                                            Prostaglandin-E  of Example                                                                          Prostaglandin F                                   __________________________________________________________________________    238  11-deoxyprostaglandin methyl                                                                   81    11-deoxyprostaglandin F.sub.2α                   ester (Ex. 46)                                                           239  11-deoxy-11α-vinylprosta-                                                                81    11-deoxy-11α-vinylprostaglandin                                         F.sub.2α                                         glandin E.sub.2 methyl ester                                                  (Ex. 28a)                                                                240  11-deoxy-11α-hydroxymethyl-                                                              80    11-deoxy-11α-hydroxymethylprosta-                prostaglandin-E.sub.2 (Ex. 83)                                                                       glandin-F.sub.2α                            241  11-deoxy-11α-hydroxymethyl-                                                              80    11-deoxy-11α-hydroxymethylprosta-                prostaglandin-E.sub.2 (Ex. 184)                                                                      glandin-F.sub.2α                            242  11α-acetylthio-11-deoxy-                                                                 80    11α-acetylthio-11-deoxyprosta-                   prostaglandin-E.sub.2 (Ex. 14)                                                                       glandin-F.sub.2α                            243  11-deoxy-11α-ethylprosta-                                                                81    11-deoxy-11α-ethylprostaglandin-F.sub.2.                                alpha.                                                 glandin-E.sub.2 methyl ester                                                  (Ex. 20)                                                                 244  11-deoxy-11,15-bisdeoxy-11,                                                                    81    11,15-bisdeoxy-11,15-dimethylprosta-                   15-dimethylprostaglandin-                                                                            glandin-F.sub.2α                                 E.sub.2 (Ex. 17)                                                         245  11-deoxy-11α-(1-hydroxy-                                                                 80    11-deoxy-11α-(1-hydroxy-1-methyl-                1-methylethyl)prosta-  ethyl)prostaglandin-F.sub.2α                     glandin-E.sub.2 (Ex. 184A)                                               __________________________________________________________________________    Ex-  Starting 11α-alkylthio-11-                                                               Method                                                                              Product                                           ample                                                                              deoxyprostaglandin E                                                                           of Example                                                                          11α-alkylthio-11-deoxyprostaglandin         __________________________________________________________________________                                F                                                 246  l-11-deoxy-11α-ethylthio-                                                                80    l-11-deoxy-11α-ethylthioprostaglandin-F.                                sub.3α                                           prostaglandin-E.sub.3 (Ex. 115)                                          247  l-11-deoxy-11α-methylthio-                                                               80    l-11-deoxy-11α-methylthio-15-epi-prosta-         15-epi-prostaglandin-E.sub.2                                                                         glandin-F.sub.2α                                 (Ex. 116)                                                                248  l-11-deoxy-11α-(1-propyl-                                                                81    l-11-deoxy-11α-(propylthio)-15-epi-O-ace                                tyl-                                                   thio)-15-epi-O-acetyl- prostaglandin-F.sub.2α methyl ester              prostaglandin-E.sub.2 methyl                                                  ester (Ex. 117)                                                          249  dl-11-deoxy-11α-butylthio-                                                               80    dl-11-deoxy-11α-butylthioprostaglandin-F                                .sub.1α                                          prostaglandin-E.sub.1 (Ex. 118)                                          250  l-11-deoxy-11α-methylthio-                                                               81    l-11-deoxy-11α-methylthioprostaglandin-F                                .sub.1α                                          prostaglandin-E.sub.1 methyl                                                                         methyl ester                                           ester (Ex. 119)                                                          251  l-11-deoxy-11α-ethylthio-15-                                                             81    l-11-deoxy-11α-ethylthio-15-methylprosta                                glandin-                                               methylprostaglandin-E.sub.2                                                                          F.sub.2α methyl ester                            methyl ester (Ex. 120)                                                   252  l-11-deoxy-11α-propylthiol-                                                              80    l-11-deoxy-11α-propylthiol-16,16-dimethy                                l-                                                     16,16-dimethylprosta-  prostaglandin-F.sub.2α                           glandin-E.sub.2 (Ex. 121)                                                253  l-11-deoxy-11α-ethylthio-                                                                80    l-11-deoxy-11α-ethylthio-16(S)-methylpro                                sta-                                                   16(S)-methylprostaglandin-                                                                           glandin-F.sub.2α                                 E.sub.2 (Ex. 122)                                                        254  l-11-deoxy-11α-methylthio-                                                               80    l-11-deoxy-11α-methylthio-16,16-difluoro                                -                                                      16,16-difluoroprostaglandin-                                                                         prostaglandin-F.sub.2α                           E.sub.2 (Ex. 123)                                                        255  l-11-deoxy-11α-methylthio-                                                               80    l-11-deoxy-11α-methylthio-16-fluoroprost                                a-                                                     16-fluoroprostaglandin-                                                                              glandin-F.sub.2α                                 E.sub.2 (Ex. 124)                                                        256  l-11-deoxy-11α-methylthiol-                                                              80    l-11-deoxy-11α-methylthiol-20-ethylprost                                a-                                                     20-ethylprostaglandin-E.sub.2                                                                        glandin-F.sub.2α                                 (Ex. 125)                                                                257  dl-11-deoxy-11α-ethylthio-                                                               80    dl-11-deoxy-11α-ethylthio-17,20-tetranor                                -16-                                                   17,20-tetranor-16-p-   p-fluorophenoxyprostaglandin-F.sub.2α            fluorophenoxyprostaglandin-                                                   E.sub.2 (Ex. 126)                                                        258  dl-11-deoxy-11α-methylthio-                                                              80    dl-11-deoxy-11α-methylthio-17,20-tetrano                                r-16-                                                  17,20-tetranor-16-m-tri-                                                                             m-trifluoromethylphenoxyprostaglandin-F.sub.2.                                alpha.                                                 fluoromethylphenoxyprosta-                                                    glandin-E.sub.2 (Ex. 127)                                                259  l-11-deoxy-11α-butylthio-                                                                80    l-11-deoxy-11α-butylthio-17,20-tetranor-                                16-m-                                                  17,20-tetranor-16-m-tri-                                                                             trifluoromethylphenoxyprostaglandin-F.sub.2.al                                pha.                                                   fluoromethylphenoxyprosta-                                                    glandin-E.sub.2 (Ex. 128)                                                260  l-11-deoxy-11α-methylthio-                                                               80    l-11-deoxy-11α-methylthio-17,20-tetranor                                -16-m-                                                 17,20-tetranor-16-m-chloro-                                                                          chlorophenoxyprostaglandin-F.sub.2α              phenoxyprostaglandin-E.sub.2                                                  (Ex. 129)                                                                __________________________________________________________________________    Ex-  Starting 11-Substituted-11-                                                                    Method                                                                              Product                                           ample                                                                              deoxyprostaglandin E                                                                           of Example                                                                          11-Substituted-11-deoxyprostaglandin              __________________________________________________________________________                                F                                                 261  l-11-deoxy-11α-methylprosta-                                                             80    l-11-deoxy-11α-methylprostaglandin-F.sub                                .3α                                              glandin-E.sub.3 (Ex. 130)                                                262  l-11-deoxy-11α-methylprosta-                                                             81    l-11-deoxy-11α-methylprostaglandin-F.sub                                .2α                                              glandin-E.sub.2 methyl ester                                                                         methyl ester                                           (Ex. 131)                                                                263  l-11-deoxy-11α-ethyl-15-epi-                                                             80    l-11-deoxy-11α-ethyl-15-epi-prostaglandi                                n-                                                     prostaglandin-E.sub.2 (Ex. 132)                                                                      F.sub.2α                                    264  dl-11-deoxy-11α-phenylprosta-                                                            81    dl-11-deoxy-11α-phenylprostaglandin-E.su                                b.2α and                                         glandin E.sub.2 and dl-11-deoxy-                                                                     dl-11-deoxy-11α-phenylprostaglandin-F.su                                b.2α methyl                                      11-phenylprostaglandin-E.sub.2                                                                       ester                                                  methyl ester (Ex. 133)                                                   265  l-11-deoxy-11α-methyl-15-methyl-                                                         81    l-11-deoxy-11α-methyl-15-methylprostagla                                ndin-                                                  prostaglandin-E.sub.2 methyl                                                                         F.sub.2α methyl ester                            ester (Ex. 134)                                                          266  l-11-deoxy-11α-methyl-16,16-                                                             81    l-11-deoxy-11α-methyl-16,16-dimethylpros                                ta-                                                    dimethylprostaglandin-E.sub.1                                                                        glandin-F.sub.1α methyl ester                    methyl ester (Ex. 135)                                                   267  l-11-deoxy-11α-vinyl-16(S)-                                                              80    l-11-deoxy-11α-vinyl-16(S)-methylprosta-         methylprostaglandin-E.sub.2                                                                          glandin-F.sub.2α                                 (Ex. 136)                                                                __________________________________________________________________________    Ex-  Starting 11-Substituted-11-                                                                    Method                                                                              Product                                           ample                                                                              deoxyprostaglandin-E                                                                           of Example                                                                          11-Substituted-11-deoxyprostaglandin              __________________________________________________________________________                                F                                                 268  l-11-deoxy-11α-(1-butenyl)-                                                              80    l-11-deoxy-11α-(1-butenyl)-16-fluoropros                                ta-                                                    16-fluoroprostaglandin-E.sub.2                                                                       glandin-F.sub.2α                                 (Ex. 137)                                                                269  l-11-deoxy-11α-propenyl-20-                                                              80    l-11-deoxy-11α-propenyl-20-ethylprostagl                                andin-                                                 ethylprostaglandin-E.sub.2                                                                           F.sub.2α                                         (Ex. 138)                                                                270  l-11-deoxy-11α-methyl-17,-                                                               80    l-11-deoxy-11α-methyl-17,20-tetranor-16-                                m-tri-                                                 20-tetranor-16-m-trifluoro-                                                                          fluoromethylphenylprostaglandin-F.sub.2α         methylphenylprostaglandin-                                                    E.sub.2 (Ex. 139)                                                        271  l-11-deoxy-11α-methyl-17,-                                                               80    l-11-deoxy-11α-methyl-17,20-tetranor-16-                                m-                                                     20-tetranor-16-m-chloro-                                                                             chlorophenoxyprostaglandin-F.sub.2α              phenoxyprostaglandin-E.sub.2                                                  (Ex. 140)                                                                271A l-11-deoxy-11α-vinyl-17,-                                                                80    l-11-deoxy-11α-vinyl-17,20-tetranor-16-m                                -tri-                                                  20-tetranor-16-m-trifluoro-                                                                          fluoromethylphenoxyprostaglandin-F.sub.2.alpha                                .                                                      methylphenoxyprostaglandin-                                                   E.sub.2 (Ex. 140A)                                                       271B l-11-deoxy-11α-vinyl-17,-                                                                80    l-11-deoxy-11α-vinyl-17,20-tetranor-16-m                                -                                                      20-tetranor-16-m-chloro-                                                                             chlorophenoxyprostaglandin-F.sub.2α              phenoxyprostaglandin-E.sub.2                                                  (Ex. 140B)                                                               271C l-11-deoxy-11α-vinyl-17,20-                                                              80    l-11-deoxy-11α-vinyl-17,20-tetranor-16-p                                -fluoro-                                               tetranor-16-p-fluorophen-                                                                            phenoxyprostaglandin-F.sub.2α                    oxyprostaglandin-E.sub.2                                                      (Ex. 140C)                                                               271D l-11-deoxy-11α-vinyl-16,16-                                                              80    l-11-deoxy-11α-vinyl-16,16-dimethylprost                                a-                                                     dimethylprostaglandin-E.sub.2                                                                        glandin-F.sub.2α                                 (Ex. 140D)                                                               __________________________________________________________________________    Ex-  Starting 13,14-dihydro-                                                                        Method                                                  ample                                                                              prostaglandin E.sub.1                                                                          of Example                                                                          Product 13,14-dihydroprostaglandin                                            F.sub.1α                                    __________________________________________________________________________    272  l-11-deoxy-11α-methyl-13,14-                                                             81    l-11-deoxy-11α-methyl-13,14-dihydro-15-m                                ethyl-                                                 dihydro-15-methyl-prosta-                                                                            prostaglandin-F.sub.1α methyl ester         273  l-11-deoxy-11α-ethyl-15-epi-                                                             80    l-11-deoxy-11α-ethyl-15-epi-13,14-dihydr                                oprostta-                                              13,14-dihydroprostaglandin-                                                                          glandin-F.sub.1α                                 E.sub.1 (Ex. 142)                                                        274  l-11-deoxy-11α-methyl-13,14-                                                             81    l-11-deoxy-11α-methyl-13,14-dihydro-16,1                                6-di-                                                  dihydro-16,16-dimethyl-                                                                              methylprostaglandin-F.sub.1α methyl                                     ester                                                  prostaglandin-E.sub.1 methyl                                                  ester (Ex. 143)                                                          275  l-11-deoxy-11α-phenyl-13,14-di-                                                          81    l-11-deoxy-11α-phenyl-13,14-dihydroprost                                a-                                                     hydroprostaglandin-E.sub.1 methyl                                                                    glandin-F.sub.1α methyl ester                    ester (Ex. 144)                                                          276  l-11-deoxy-11α-methyl-13,14-                                                             80    l-11-deoxy-11α-methyl-13,14-dihydro-17,2                                0-tetra-                                               dihydro-17,20-tetranor-16-                                                                           nor-16-m-trifluoromethylphenoxyprostaglandin-          m-trifluoromethylphenoxy-                                                                            F.sub.1α                                         prostaglandin-E.sub.1                                                    __________________________________________________________________________    Ex-  11α/β-cyano-11-deoxy-                                                               Method                                                  ample                                                                              prostaglandin E  of Example                                                                          Product 11α/β-cyano-11-deoxyprostag                                landin F                                          __________________________________________________________________________    277  l-11-deoxy-11α-cyanoprosta-                                                              80    l-11-deoxy-11α-cyanoprostaglandin-F.sub.                                3α and                                           glandin-E.sub.3 and l-11-deoxy-                                                                      l-11-deoxy-11β-cyanoprostaglandin-F.sub.3                                β                                                 11β-cyanoprostaglandin-E.sub.3                                           (Ex. 158)                                                                278  dl-11-deoxy-11α-cyanoprosta-                                                             80    dl-11-deoxy-11α-cyanoprostaglandin-F.sub                                .2α and                                          glandin-E.sub.2 and dl-11-deoxy-                                                                     dl-11-deoxy-11β-cyanoprostaglandin-F.sub.                                2β                                                11β-cyanoprostaglandin-E.sub.2                                           (Ex. 159)                                                                279  l-11-deoxy-11α-cyano-15-                                                                 81    l-11-deoxy-11α-cyano-15-methylprostaglan                                din-F.sub.2α                                     methylprostaglandin-E.sub.2                                                                          and l-11-deoxy-11β-cyano-15-methylprosta-         and l-11-deoxy-11β-cyano-                                                                       glandin-F.sub.2β methyl esters                    15-methylprostaglandin-                                                       E.sub.2 methyl esters (Ex. 160)                                          280  l-11-deoxy-11α-cyano-16,16-                                                              80    l-11-deoxy-11α-cyano-16,16-dimethylprost                                a-                                                     dimethylprostaglandin-E.sub.2                                                                        glandin-F.sub.2β  and l-11-deoxy-11β                                -cyano-16,16-                                          and l-11-dioxy-11β-cyano-                                                                       dimethylprostaglandin-F.sub.2α                   16,16-dimethylprosta-                                                         glandin-E.sub.2 (Ex. 161)                                                281  l-11-deoxy-11α-cyano-16(S)-                                                              80    l-11-deoxy-11α-cyano-16(S)-methylprostag                                landin-                                                methylprostaglandin-E.sub.2                                                                          F.sub.2α and l-11-deoxy-11β-cyano-1                                6(S)-methyl                                            and l-11-deoxy-11β-cyano-                                                                       prostaglandin-F.sub.2β                            16(S)-methylprostaglandin-                                                    E.sub.2 (Ex. 162)                                                        __________________________________________________________________________    Ex-  Starting 11α/β-cyano-11-                                                            Method                                                  ample                                                                              deoxyprostaglandin-E                                                                           of Example                                                                          Product 11α/β-cyano-11-deoxyprostag                                landin F                                          __________________________________________________________________________    282  l-11-deoxy-11α-cyano-16,16-                                                              80    l-11-deoxy-11α-cyano-16,16-difluoroprost                                a-                                                     difluoroprostaglandin-E.sub.2                                                                        glandin-F.sub.2α and l-11-deoxy-11β                                -cyano-16,16-di-                                       and l-11-deoxy-11β-cyano-16,                                                                    fluoroprostaglandin-F.sub.2α                     16-difluoroprostaglandin-                                                     E.sub.2 (Ex. 163)                                                        283  l-11-deoxy-11α-cyano-16-                                                                 80    l-11-deoxy-11α-cyano-16-fluoroprostaglan                                din-F.sub.2α                                     fluoroprostaglandin-E.sub.2                                                                          and d-11-deoxy-11β-cyano-16-fluoroprosta-                                n                                                      and d-11-deoxy-11β-cyano-                                                                       glandin-F.sub.2α                                 16-Fluoroprostaglandin-                                                       E.sub.2 (Ex. 164)                                                        284  dl-11-deoxy-11α-cyano-17,20-                                                             80    di-11-deoxy-11α-cyano-17,20-tetranor-16-                                p-                                                     tetranor-16-p-fluorophen-                                                                            fluorophenoxyprostaglandin-F.sub.2α and                                 dl-11-deoxy-                                           oxyprostaglandin-E.sub.2 and dl-                                                                     11β-cyano-17,20-tetranor-16-p-fluoropheno                                xy-                                                    11-deoxy-11β-cyano-17,20-                                                                       prostaglandin-F.sub.2α                           tetranor-16-p-fluorophen-                                                     oxyprostaglandin-E.sub.2 (Ex. 165)                                       285  l-11-deoxy-11α-cyano-17,20-                                                              80    l-11-deoxy-11α-cyano-17,20-tetranor-16-m                                -tri-                                                  tetranor-16-m-trifluoro-                                                                             fluoromethylphenoxyprostaglandin-F.sub.2.alpha                                . and l-11-                                            methylphenoxyprostaglandin-                                                                          deoxy-11β-cyano-17,20-tetranor-16-m-trifl                                uoro-                                                  E.sub.2 and l-11-deoxy-11β-                                                                     methylphenoxyprostaglandin-F.sub.2α              cyano-17,20-tetranor-16-                                                      m-trifluoromethylphenoxy-                                                     prostaglandin-E.sub. 2 (Ex. 166)                                         __________________________________________________________________________    Ex-  Starting 11α/β-cyano-11-                                                            Method                                                  ample                                                                              deoxyprostaglandin E                                                                           of Example                                                                          Product 11α/β-cyano-11-deoxyprostag                                landin F                                          __________________________________________________________________________    286  l-11-deoxy-11α-cyano-17,20-                                                              80    l-11-deoxy-11α-cyano-17,20-tetranor-16-m                                -chloro-                                               tetranor-16-m-chlorophenoxy-                                                                         phenoxyprostaglandin-F.sub.2α and                                       l-11-deoxy-11-                                         prostaglandin-E.sub.2 and l-11-                                                                      cyano-17,20-tetranor-16-m-chlorophenoxyprosta-                                a                                                      deoxy-11β-cyano-17,20-tetra-                                                                    glandin-F.sub.2β                                  nor-16-m-chlorophenoxyprosta-                                                 glandin-E.sub.2 (Ex. 167)                                                __________________________________________________________________________    Ex-  Starting 11-Substituted-11-                                                                    Method                                                                              Product                                           ample                                                                              deoxy-prostaglandin E                                                                          of Example                                                                          11-Substituted-11-deoxyprostaglandin              __________________________________________________________________________                                F                                                 287  dl-11-deoxy-11α-hydroxyprosta-                                                           80    dl-11-deoxy-11α-hydroxymethylprostagland                                in-F.sub.2α                                      glandin-E.sub.2 ; dl-11-deoxy-11β-                                                              dl-11-deoxy-11β-hydroxymethylprostaglandi                                n-F.sub.2α                                       hydroxymethylprostaglandin-E.sub.2                                                                   and dl-8-iso-11α-hydroxymethylprostaglan                                din-F.sub.2α                                     (Ex. 174)                                                                288  l-11-deoxy-11α-hydroxymethyl-15-                                                         81    l-11-deoxy-11α-hydroxymethyl-15-methylpr                                osta-                                                  methylprostaglandin-E.sub.2 methyl                                                                   glandin-F.sub.2α  methyl ester;                                         l-11-deoxy-11β-                                   ester; l-11-deoxy-11β-hydroxy-                                                                  hydroxymethyl-15-methylprostaglandia-F.sub.2.a                                lpha.  and                                             methyl-15-methylprostaglandin-                                                                       8-iso-11-deoxy-11α-hydroxymethyl-15-meth                                yl-                                                    E.sub.2 and 8-iso-11-deoxy-11α-                                                                prostaglandins-F.sub.2α methyl ester             hydroxymethyl-15-methylprosta-                                                glandins-E.sub.2 methyl ester                                                 (Ex. 175)                                                                289  l-11-deoxy-11α-(1-hydroxy-                                                               80    l-11-deoxy-11α-(1-hydroxymethyl)-16,16-d                                imethyl-                                               methyl)-16,16-dimethylprosta-                                                                        prostaglandin-F.sub.1α ;                                                l-11-deoxy-11α-(1-hydroxy-                       glandin-E.sub.1 ; l-11-deoxy-11β                                                                methyl)-16,16-dimethylprostaglandin-F.sub.1.al                                pha.  and                                              (1-hydroxymethyl)-16,16-dl-                                                                          8-iso-11-deoxy-11α-(hydroxymethyl)-16,16                                -dl-                                                   methylprostaglandin-E.sub.1 and                                                                      methylprostaglandin-F.sub.1α                     8-oxo-11-deoxy-11α-(hydroxy-                                            methyl)-16,16-dimethylprosta-                                                 glandin-E.sub.1  (Ex. 176)                                               __________________________________________________________________________    Ex-  Starting 11-substituted-11-                                                                    Method                                                                              Product                                           ample                                                                              deoxyprostaglandin E                                                                           of Example                                                                          11-Substituted-11-deoxyprostaglandin              __________________________________________________________________________                                F                                                 290  l-11-deoxy-11α-hydroxy-                                                                  80    l-11-deoxy-11α-hydroxymethyl-16(R)-methy                                1prosta-                                               methyl-16(R)-methy1prosta-                                                                           glandin-F.sub.2 ; l-11-deoxy-11β-hydroxym                                ethyl-16(R)-                                           glandin-E.sub.2 ; l-11-deoxy-11β-                                                               methylprostaglandin-F.sub.2α  and                                       8-iso-11-deoxy-                                        hydroxymethyl-16(R)-   11α-hydroxymethyl-16(R)-methylprostaglan                                din-                                                   methylprostaglandin-E.sub.2                                                                          F.sub.2α                                         and dl-8-iso-11α-hydroxymethyl-                                         prostaglandin-E.sub.2 (Ex. 177)                                          291  l-11-deoxy-11α-hydroxy-                                                                  80    l-11-deoxy-11α-hydroxymethyl-16,16-diflu                                oro-                                                   methyl-16,16-difluoro- prostaglandin-F.sub.2α ;                                                l-11-deoxy-11β-hydroxy-                           prostaglandin-E.sub.2 ; l-11-                                                                        methyl-16,16-difluoroprostaglandin-F.sub.2                                    and                                                    deoxy-11β-hydroxymethyl-                                                                        8-iso-11-deoxy-11α-hydroxymethyl-16,16-d                                ifluoro-                                               16,16-difluoroprosta-  prostaglandin-F.sub.2α                           glandin-E.sub.2 and 8-iso-11-                                                 deoxy-11β-hydroxymethyl-                                                 16,16-difluoroprosta-                                                         glandin-E.sub.2 (Ex. 178)                                                __________________________________________________________________________    Ex-                   Method                                                  ample                                                                              Starting prostaglandin E                                                                       of Example                                                                          Product Prostaglandin Fα                    __________________________________________________________________________    292  l-11-deoxy-11α-(1-hydroxy-                                                               80    l-11-deoxy-11α-(1-hydroxyethyl)-13-dihyd                                ro-                                                    ethyl)-13-dihydroprosta-                                                                             prostaglandin-F.sub.1α  and                                             11-deoxy-11α-(1-hydroxy-                         glandin-E.sub.1 and 11-deoxy-11α-                                                              ethyl)-13-dihydroprostaglandin-F.sub.1α                                 and 8-iso-                                             (1-hydroxymethyl)-13-di-                                                                             (1-hydroxyethyl)-13-dihydro-                           hydroprostaglandin-E.sub.1 and                                                                       prostaglandin-F.sub.1                                  8-iso-11-deoxy-11α-(1-                                                  hydroxyethyl)-13-dihydro-                                                     prostaglandin-E.sub.1 (Ex. 169)                                          293  l-11-deoxy-11α-(1-hydroxy-1-                                                             80    l-11-dioxy-11α-(1-hydroxy-1-methylethyl)                                -                                                      methylethyl)prostaglandin-                                                                           prostaglandin-F.sub.1α                           E.sub.1 (Ex. 170)                                                        294  l-11-deoxy-11α-hydroxy-                                                                  80    l-11-deoxy-11α-hydroxymethyl-prostagland                                in-F.sub.3α                                      methyl-prostaglandin-E.sub.3                                                                         and l-11-deoxy-11α-hydroxymethylprostagl                                andin-                                                 and l-11-deoxy-11α-hydroxy-                                                                    F.sub.3α and 8-iso-11-deoxy-11α-hy                                droxymethylprosta-                                     methylprostaglandin-E.sub.2 and                                                                      glandin-F.sub.3α                                 8-iso-11-deoxy-11α-hydroxy-                                             methylprostaglandin-E.sub.3                                                   (Ex. 171)                                                                295  l-11-deoxy-11α-hydroxy-                                                                  80    l-11-deoxy-11α-hydroxymethyl-15-epiprost                                a-                                                     methyl-15-epiprostaglandin-                                                                          glandin-F.sub.2α and l-11-deoxy-11.alpha                                .-hydroxymethyl-                                       E.sub.2 and l-11-deoxy-11α-hy-                                                                 15-epiprostaglandin-F.sub.2α and                                        8-iso-11-deoxy-11α                               droxymethyl-15-epiprosta-                                                                            hydroxymethyl-15-epiprostaglandin-F.sub.2.alph                                a.                                                     glandin-E.sub.2 and 8-iso-11-                                                 deoxy-11α-hydroxymethyl-15-                                             epiprostaglandin-E.sub.2 (Ex. 172)                                       296  l-11-deoxy-11α-(1-hydroxy-1-                                                             81    l-11-deoxy-11α-(1-hydroxy-1-methylethyla                                cetyl-                                                 methylethylacetylprosta-                                                                             prostaglandin-F.sub.2α  methyl ester             glandin-E.sub.2 methyl ester                                                  (Ex. 173)                                                                297  l-11-deoxy-11α-hydroxy-                                                                  80    l-11-deoxy-11α-hydroxymethyl-20-ethylpro                                sta-                                                   methyl-20-ethylprostaglandin-                                                                        glandin-F.sub.2 ; l-11-deoxy-11β-hydroxym                                ethyl-20-                                              E.sub.2 ; l-11-deoxy-11β-hydroxy-                                                               ethylprostglandin-F.sub.2α  and                                         8-iso-11-deoxy-                                        methyl-20-ethylprostaglandin-                                                                        11α-hydroxymethyl-20-ethylprostaglandin-                                F.sub.2α                                         E.sub.2 and 8-iso-11-deoxy-11α-                                         hydroxymethyl-20-ethyl-                                                       prostaglandin-E.sub.2 (Ex. 179)                                          298  dl-11-deoxy-11α-hydroxy-                                                                 80    dl-11-deoxy-11α-hydroxymethyl-17,20-tetr                                anor-                                                  methyl-17,20-tetranor-16-m-                                                                          16-m-trifluoromethylphenoxyprostaglandin-              trifluoromethylphenoxy-                                                                              F.sub.2α ; dl-11-deoxy-11β-hydroxym                                ethyl-17,20-                                           prostaglandin-E.sub.2 ; dl-11-                                                                       tetranor-16-m-trifluoromethylphenoxyprosta-            deoxy-11β-hydroxymethyl-                                                                        glandin-F.sub.2α  and                                                   dl-8-iso-11-deoxy-11α-hydroxy-                   17,20-tetranor-16-m-tri-                                                                             methyl-17,20-tetranor-16-m-trifluoromethyl-            fluoromethylphenoxyprosta-                                                                           prostaglandin-F.sub.2α                           glandin-E.sub.2 and dl-8-iso-                                                 11-deoxy-11α-hydroxymethyl-                                             17,20-tetranor-16-m-tri-                                                      fluoromethylprostaglandin-                                                    E.sub.2 (Ex. 180)                                                        299  l-11-deoxy-11α-(-hydroxy-1-                                                              80    l-11-deoxy-11α-(1-hydroxy-1-methylethyl)                                -                                                      methylethyl)-17,20-tetranor-                                                                         17,20-tetranor-16-p-fluorophenoxyprosta-               16-p-fluorophenoxyprosta-                                                                            glandin-F.sub.2                                        glandin-E.sub.2 (Ex. 181)                                                300  l-11-deoxy-11α-hydroxymethyl-                                                            80    l-11-deoxy-11α-hydroxymethyl-17,20-tetra                                nor-                                                   17,20-tetranor-16-m-chloro-                                                                          16-m-chlorophenoxyprostaglandin-F.sub.2α                                 ; l-11-                                               phenoxyprostaglandin-E.sub.2 ; 1-                                                                    11β-hydroxymethyl-17,20-tetranor-16-m-            11-deoxy-11β-hydroxymethyl-                                                                     chlorophenoxyprostaglandin-F.sub.2α                                     and l-8-iso-                                           17,20-tetranor-16-m-chloro-                                                                          11-deoxy-11α-hydroxymethyl-17,20-tetrano                                r-                                                     chlorophenoxyprostaglandin-                                                                          16-m-chlorophenoxyprostaglandin-F.sub.2α                                e                                                      E.sub.2 and l-8-iso-11-deoxy-11α-                                       hydroxymethyl-17,20-tetranor-                                                 16-m-chlorophenoxyprosta-                                                     glandin-E.sub.2                                                          301  l-11-deoxy-11α-(1,3-dioxoan-                                                             80    l-11-deoxy-11α-(1,3-dioxolan-2-yl)-13-di                                hyro-                                                  2-yl)-1,3-dihydroprosta-                                                                             prostaglandin-F.sub.1α                           glandin-E.sub.1 (Ex. 186)                                                302  l-11-deoxy-11α-(2-methyl-                                                                80    l-11-deoxy-11α-(2-methyl-1,3-dioxolan-2-                                yl)-                                                   1,3-dioxolan-2-yl)prosta-                                                                            prostaglandin-F.sub.1α                           glandin-E.sub.1 (Ex. 187)                                                303  l-11-deoxy-11α-(1,3-dioxolan-                                                            80    l-11-deoxy-11α-(1,3-dioxolan-2-yl)-prost                                a-                                                     2-yl)-prostaglandin-E.sub.3                                                                          glandin-F.sub.3α                            304  l-11-deoxy-11α-(1,3-dioxolan-                                                            80    l-11-deoxy-11α-(1,3-dioxolan-2-yl)-15-ep                                i-                                                     2-yl)-15-epi-prostaglandin-                                                                          prostaglandin-F.sub.2α                           E.sub.2 (Ex. 189)                                                        305  dl-11-deoxy-11α-(1,3-dioxolan-                                                           80    dl-11-deoxy-11α-(1,3-dioxolan-2-yl)-pros                                ta-                                                    2-yl)-prostaglandin-E.sub.2                                                                          glandin-F.sub.2α                                 (Ex. 190)                                                                306  l-11-deoxy-11α-(1,3-dioxolan-                                                            81    l-11-deoxy-11α-(1,3-dioxolan-2-yl)-15-me                                thyl-                                                  2-yl)-15-methylprostaglandin-                                                                        prostaglandin-F.sub.1α methyl ester              E.sub.1 methylester (Ex. 191)                                            307  l-11-deoxy-11α-(2-methyl-                                                                80    l-11-deoxy-11α-(2-methyl-1,3-dioxolan-2-                                yl)-                                                   1,3-dioxolan-2-yl)-16,16-                                                                            16,16-dimethylprostaglandin-F.sub.2α             dimethylprostaglandin-E.sub.2                                            308  l-11-deoxy-11α-(1,3-dioxolan-                                                            80    l-11-deoxy-11α-(1,3-dioxolan-2-yl)-16-(R                                )methyl-                                               2-yl)-16(R)-methylprosta-                                                                            prostaglandin-F.sub.2α                           glandin-E.sub.2 (Ex. 193)                                                309  l-11-deoxy-11α-(1,3-dioxolan-                                                            80    l-11-deoxy-11α-(1,3-dioxolan-2-yl)-16,16                                -di-                                                   2-yl)-16,16-difluoroprosta-                                                                          fluoroprostaglandin-F.sub.2α                     glandin-E.sub.2 (Ex. 194)                                                310  l-11-deoxy-11α-(1,3-dioxolan-                                                            80    l-11-deoxy-11α-(1,3-dioxolan-2-yl)-20-et                                hyl-                                                   2-yl)-20-ethylprostaglandin-                                                                         prostaglandin-F.sub.2α                           E.sub.2 (Ex. 195)                                                        311  dl-11-deoxy-11α-(1,3-                                                                    80    dl-11-deoxy-11α-(1,3-dioxolan-2-yl)-17,2                                0-                                                     dioxolan-2-yl)-17,20-  tetranor-16-m-trifluoromethylphenoxyprosta-            tetranor-16-m-trifluoro-                                                                             glandin-F.sub.2α                                 methylphenoxyprostaglandin-                                                   E.sub.2 (Ex. 196)                                                        312  l-11-deoxy-11α-(1,3-dioxo-                                                               80    l-11-deoxy-11α-(1,3-dioxolan-2-yl)-17,20                                -                                                      lan-2-yl)-17,20-tetranor-                                                                            tetranor-16-p-fluorophenoxyprostaglandin-F.sub                                .2α                                              16-p-fluorophenoxyprosta-                                                     glandin-E.sub.2 (Ex. 197)                                                313  l-11-deoxy-11α-(1,3-dioxo-                                                               80    l-11-deoxy-11α-(1,3-dioxolan-2-yl)-17,20                                -                                                      lan-2-yl)-17,20-tetranor-                                                                            tetranor-16-m-chlorophenoxyprostaglandin-F.sub                                .2α                                              16-m-chlorophenoxyprosta-                                                     glandin-F.sub.2 (Ex. 198)                                                __________________________________________________________________________    Ex-  Starting 11-deoxy-11α/β-                                                            Method                                                                              Product 11-deoxy-11α/β-mercaptopros                                ta-                                               ample                                                                              alkanoylthioprostaglandin E                                                                    of Example                                                                          glandin E                                         __________________________________________________________________________    314  l-11-deoxy-11α-propanoylthio-                                                            80    l-11-deoxy-11α-mercapto-13-dihydroprosta                                glandin-                                               13-dihydroprostaglandin-F.sub.1                                                                      F.sub.1α and 11-deoxy-11β-propanoyl                                yhiol-13-di-                                           and 11-deoxy-11β-propanoylthio-                                                                 dihydroprostaglandin-F.sub.1α                    13-dihydroprostaglandin-E.sub.1                                               (Ex. 223)                                                                315  l-11-deoxy-11α-acetylthioprosta-                                                         80    l-11-deoxy-11α-mercaptoprostaglandin-F.s                                ub.2α and                                        glandin-E.sub.3 and l-11-deoxy-11β-                                                             l-11-deoxy-11β-mercaptoprostaglandin-F.su                                b.3α                                             acetylthioprostaglandin-E.sub.3                                               (Ex. 224)                                                                316  l-11-deoxy-11α-acetylthio-                                                               80    l-11-deoxy-11α-mercaptoprostaglandin-F.s                                ub.  2α                                          prostaglandin-E.sub.2 methyl ester                                                                   methyl ester and l-11-deoxy-11β-mercaptop                                rosta-                                                 and l-11-deoxy-11β-acetylthio-                                                                  glandin-F.sub.2α methyl ester                    prostaglandin-E.sub.2 methyl ester                                            (Ex. 225)                                                                317  l-11-deoxy-11α-acetylthio-                                                               80    l-11-deoxy-11α-mercaptoprostaglandin-15-                                epi-                                                   15-epi-prostaglandin-E.sub.2 and                                                                     prostaglandin-F.sub.2α and                                              l-11-deoxy-11β-mercapto-                          l-11-deoxy-11β-acetylthio-                                                                      15-epiprostaglandin-F.sub.2α                     15-epiprostaglandin-E.sub.2                                                   (Ex. 226)                                                                318  dl-11-deoxy-11α-acetylthio-                                                              80    dl-11-deoxy-11α-mercaptoprostaglandin-E.                                sub.1α and                                       prostaglandin-E.sub.1 and dl-11-                                                                     dl-11-deoxy-11β-mercaptoprostaglandin-F.s                                ub.1α                                            deoxy-11β-acetylthiol-                                                   prostaglandin-E.sub.1 (Ex. 227)                                          319  l-11-deoxy-11α-acetylthio-                                                               80    l-11-deoxy-11α-mercapto-16,16-dimethylpr                                osta-                                                  16,16-dimethylprostaglandin-                                                                         glandin-F.sub.1α and l-11-deoxy-11β                                -mercapto-16,16-                                       E.sub.1 and l-11-deoxy-11β-acetyl-                                                              dimethylprostaglandin-F.sub.1α                   thio-16,16-dimethylprosta-                                                    glandin-E.sub.1 (Ex. 228)                                                320  l-11-deoxy-11α-acetylthio-                                                               80    l-11-deoxy-11α-mercapto-16,16-dimethylpr                                osta-                                                  16,16-dimethylprostaglandin-                                                                         glandin-F.sub.2α and l-11-deoxy-11β                                -mercapto-16,16-                                       E.sub.2 and l-11-deoxy-11β-                                                                     dimethylprostaglandin-F.sub.2α                   acetylthio-16,16-dimethyl-                                                    prostaglandin-E.sub.2 (Ex. 229)                                          321  l-11-deoxy-11α-acetylthiol-                                                              80    l-11-deoxy-11α-mercapto-16,16(S)-methylp                                rosta-                                                 16(S)methylprostaglandin-E.sub.2                                                                     glandin-F.sub.2α and l-11-deoxy-11β                                -mercapto-16(S)-                                       and l-11-deoxy-11β-acetyl-                                                                      methylprostaglandin-F.sub.2α                     thio-16(S)-methylprosta-                                                      glandin-E.sub.2 (Ex. 230)                                                322  l-11-deoxy-11α-acetylthio-                                                               80    l-11-deoxy-11α-mercapto-16-fluoroprostag                                landin-                                                16-fluoroprostaglandin-E.sub.2                                                                       F.sub.2α and l-11-deoxy-11β-mercapt                                o-16-fluoro-                                           and l-11-deoxy-11β-acetyl-                                                                      prostaglandin-F.sub.2α                           thio-16-fluoroprostaglandin-                                                  E.sub.2 (Ex. 231)                                                        323  l-11-deoxy-11α-acetylthio-20-                                                            80    l-11-deoxy-11α-mercapto-20-methylprostag                                landin-                                                methylprostaglandin-E.sub.2 and                                                                      E.sub.2α and l-11-deoxy-11β-mercapt                                o-20-methyl-                                           l-11-deoxy-11β-acetylthiol-20-                                                                  prostaglandin-F.sub.2α                           methylprostaglandin-E.sub.2 (Ex. 232)                                    324  dl-11-deoxy-11α-acetylthio-                                                              80    dl-11-deoxy-11α-mercapto-17,20-tetranor-                                16-m-                                                  17,20-tetranor-16-m-trifluoro-                                                                       trifluoromethylphenoxyprostaglandin-E.sub.2                                   and                                                    methylphenoxyprostaglandin-E.sub.2                                                                   dl-11-deoxy-11β-mercapto-17,20-tetranor-1                                6-m-                                                   and dl-11-deoxy-11β-acetyl-                                                                     trifluoromethylphenoxyprostaglandin-E.sub.2            thiol-17,20-tetranor-16-m-tri-                                                                       trifluoromethylphenoxyprostaglandin-E.sub.2            fluoromethylphenoxyprosta-                                                    glandin-E.sub.2 (Ex. 233)                                                325  l-11-deoxy-11α-acetylthio-                                                               80    l-11-deoxy-11α-mercapto-17,20-tetranor-1                                6-p-                                                   17,20-tetranor-16-p-fluoro-                                                                          fluorophenoxyprostaglandin-F.sub.2α and                                 l,-11-deoxy-                                           phenoxyprostaglandin-E.sub.2 and                                                                     11β-mercapto-17,20-tetranor-16-p-fluoroph                                en-                                                    l-11-deoxy-11β-acetylthiol-                                                                     oxyprostaglandin-F.sub.2α                        17,20-tetranor-16-p-fluoro-                                                   phenoxyprostaglandin-E.sub.2                                                  (Ex. 234)                                                                326  l-11-deoxy-11α-acetylthio-                                                               80    l-11-deoxy-11α-mercapto-17,20-tetranor-1                                6-m-                                                   17,20-tetranor-16-m-chloro-                                                                          chlorophenoxyprostaglandin-F.sub.2α and                                 l-11-deoxy-                                            phenoxyprostaglandin-E.sub.2                                                                         11β-mercapto-17,20-tetranor-16-m-chloro-                                 r                                                      and l-11-deoxy-11β-acetyl-                                                                      phenoxyprostaglandin-F.sub.2α                    thio-17,20-tetranor-16-m-                                                     chlorophenoxyprostaglandin-                                                   E.sub.2 (Ex. 235)                                                        __________________________________________________________________________

EXAMPLES 327-343

Hydrolysis of the starting prostaglandins of the table below by themethod of Example 217 is productive of the product prostaglandins of thetable.

    __________________________________________________________________________    Ex-                                                                           ample                                                                             Starting Prostaglandin                                                                           Product                                                __________________________________________________________________________    327 l-11-deoxy-11α-(1,3-dioxolan-2-yl)-13-                                                     l-11-deoxy-11α-(formyl)-13-dihydroprosta-            dihydroprostaglandin-F.sub.1α (Ex. 301)                                                    glandin-E.sub.1α                                 328 l-11-deoxy-11α-(2-methyl-1,3-dioxolan-                                                     l-11-deoxy-11α-(acetyl)-prostaglandin-F.sub.1                           α                                                    2-yl)-prostaglandin-F.sub.1α (Ex. 302)                              329 l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                        l-11-deoxy-11α-(formyl)-prostaglandin-F.sub.3                           α                                                    prostaglandin-F.sub.3α (Ex. 303)                                    330 l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                        l-11-deoxy-11α-(formyl)-15-epi-prostaglandin-                           s                                                          15-epi-prostaglandin-F.sub.2α (Ex. 304)                                                    F.sub.2α                                         331 dl-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                       dl-11-deoxy-11α-(formyl)-prostaglandin-F.sub.                           2α                                                   prostaglandin-F.sub.2α (Ex. 305)                                    332 l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                        l-11-deoxy-11α-(formyl)-15-methylprostaglandi                           n-                                                         15-methylprostaglandin-F.sub.1α methyl                                                     F.sub.1α methyl ester                                ester (Ex. 306)                                                           333 l-11-deoxy-11α-(2-methyl-1,3-dioxolan-                                                     l-11-deoxy-11α-(acetyl)-16,16-dimethylprosta-                           5                                                          2-yl)-16,16-dimethylprostaglandin-                                                               glandin-F.sub.2α                                     F.sub.2α (Ex. 307)                                                  334 l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                        l-11-deoxy-11α-(formyl)-16(R)-methylprosta-          16(R)-methylprostaglandin-F.sub.2α                                                         glandin-F.sub.2α                                     (Ex. 308)                                                                 335 l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                        l-11-deoxy-11α-(formyl)-16,16-difluoroprosta-                           .                                                          16,16-difluoroprostaglandin-F.sub.2α                                                       glandin-F.sub.2α                                     (Ex. 309)                                                                 336 l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                        l-11-deoxy-11α-(formyl)-20-ethylprostaglandin                           -                                                          20-ethylprostaglandin-F.sub.2α                                                             F.sub.2α                                             (Ex. 310)                                                                 337 dl-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                       dl-11-deoxy-11α-(formyl)-17,20-tetranor-16-m-                           d                                                          17,20-tetranor-16-m-trifluoromethyl-                                                             trifluoromethylphenoxyprostaglandin-F.sub.2α                            e                                                          phenoxyprostaglandin-F.sub.2α (Ex. 311)                             338 l-11-deoxy-11α -(1,3-dioxolan-2-yl)-                                                       l-11-deoxy-11α-(formyl)-17,20-tetranor-16-p-                            n                                                          17,20-tetranor-16-p-fluorophenoxy-                                                               fluorophenoxyprostaglandin-F.sub.2α                  prostaglandin-F.sub.2α (Ex. 312)                                    339 l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                        l-11-deoxy-11α-(formyl)-17,20-tetranor-16-m-                            t                                                          17,20-tetranor-16-m-chlorophenoxy-                                                               chlorophenoxyprostaglandin-F.sub.2α                  prostaglandin-F.sub.2α (Ex. 313)                                    340 l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                        l-11-deoxy-11α-(formyl)-prostaglandin-F.sub.2                           α                                                    prostaglandin-F.sub.2α (Ex. 215)                                    341 dl-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                       dl-11-deoxy-11α-(formyl)-17,20-tetranor-16-p-                           Z                                                          17,20-tetranor-16-p-fluoroprosta-                                                                fluoroprostaglandin-F.sub.2α                         glandin-F.sub.2α (Ex. 216)                                          __________________________________________________________________________    Ex-                                                                           ample                                                                             Starting E Prostaglandins                                                                        Product F Prostaglandins                               __________________________________________________________________________    342 l-11-deoxy-11β-(1,3-dioxolan-2-yl)-                                                         l-11-deoxy-11β-(formyl)-prostaglandin-F.sub.2.                           alpha.                                                     prostaglandin-F.sub.2α and F.sub.2β (Ex.                                              and F.sub.2β                                      343 l-11-deoxy-11β-(1,3-dioxolano-2-yl)-                                                        l-11-deoxy-11α-(formyl)-17,20-tetranor-16-p-                            O                                                          17,20-tetranor-16-p-fluoroprosta-                                                                fluoroprostaglandin-F.sub.2α and                                        F.sub.2β                                              glandins-F.sub.2α and F.sub.2β (Ex. 211)                       __________________________________________________________________________

We claim:
 1. A compound selected from the group consisting of anoptically active compound of the formula ##STR11## and a racemiccompound of that formula and the mirror image thereof wherein R isphenyl, phenoxy or phenoxy substituted with one or more groups selectedfrom the group consisting of lower alkyl, lower alkoxy, nitro, halo andtrifluoromethyl; R₁ is selected from the group consisting of lower alkyland lower 1-alkenyl; R₂ is selected from the group consisting ofhydrogen and an alkyl group having from 1 to 12 carbon atoms; R₃ and R₄are hydrogen; X is a divalent moiety selected from the group consistingof those of the formula ##STR12## wherein R₆ is selected from the groupconsisting of hydrogen and lower alkyl; Y is a divalent moiety selectedfrom the group consisting of those of the formula ##STR13## the moiety-C₅ -C₆ - is ethylene or cis vinylene and the moiety -C₁₃ -C₁₄ - isethylene or trans vinylene with the proviso that when -C₅ -C₆ - iscis-vinylene then -C₁₃ -C₁₄ - must be trans-vinylene; and the non-toxic,cationic salts thereof when R₂ is hydrogen.
 2. A compound according toclaim 1 wherein R is phenoxy, and phenoxy substituted with one or moregroups selected from the groups consisting of lower alkyl, lower alkoxy,nitro, halogen and trifluoromethyl.
 3. A compound according to claim 2wherein the moiety -C₅ -C₆ - is cis-vinylene and the moiety -C₁₃ -C₁₄ -is trans-vinylene.
 4. A compound according to claim 3 wherein R₁ is amethyl or ethyl group or vinyl-moiety and Y is the divalent moiety##STR14##
 5. A compound according to claim 4 wherein R₁ is methyl.
 6. Acompound according to claim 2 wherein R₁ is methyl; R₂ is hydrogen; R₃is hydrogen, R₄ is hydrogen; R is m-trifluoromethylphenoxy; -C₅ -C₆ isethylene; -C₁₃ -C₁₄ is ethylene; X is ##STR15## Y is ##STR16##11-deoxy-11α-methyl-13,14-dihydro-17,20-tetranor-16-m-trifluoromethylphenoxyprostaglandin-F₁α.
 7. A compound according to claim 2 wherein R₁ ismethyl; R₂ is hydrogen; R₃ is hydrogen; R₄ is hydrogen; R isn-trifluoromethylphenoxy; -C₅ -C₆ is ethylene; X is ##STR17## Y is##STR18##11-deoxy-11α-methyl-13,14-dihydro-17,20-tetranor-16-m-trifluoromethylphenoxyprostaglandin-F₁β.
 8. The compound according to claim 3,1-11-deoxy-11α-methyl-17,20-tetranor-16-m-chlorophenoxy-F₂.beta..
 9. Thecompound according to claim 4,1-11-deoxy-11α-vinyl-17,20-tetranor-16-m-trifluoromethylphenoxy-F.sub.2α.10. The compound according to claim 4,1-11-deoxy-11α-vinyl-17,20-tetranor-16-p-fluorophenoxy-F₂.alpha.. 11.The optically active compound according to claim 4 wherein R₁ isα-vinyl; R₂ is hydrogen; R₃ is hydrogen; R₄ is hydrogen; R ism-chlorophenoxy; C₁₃ -C₁₄ is trans-vinylene; C₅ -C₆ is cis-vinylene; Xis ##STR19## Y is ##STR20## 1α-vinyl-17-20-tetranor-16-m-chlorophenoxy-11-deoxyprostaglandin-F.sub.2α.12. The optically active compound according to claim 5 wherein R₁ isα-methyl; R₂ is hydrogen; R₃ is hydrogen; R₄ is hydrogen; R ism-chlorophenoxy; C₁₃ -C₁₄ is trans-vinylene; C₅ -C₆ is cis-vinylene; Xis ##STR21## Y is ##STR22## 1α-methyl-16-m-chlorophenoxy-17,18,19,20-tetranor-11-deoxyprostaglandin-F₂α.13. The optically active compound according to claim 5 wherein R₁ isα-methyl; R₂ is hydrogen; R₃ is hydrogen; R₄ is hydrogen; R ism-trifluoromethylphenoxy; C₁₃ -C₁₄ is trans-vinylene; C₅ -C₆ iscis-vinylene; X is ##STR23## Y is ##STR24## 1α-methyl-16-m-trifluoromethylphenoxy-17,18,19,20-tetranor-11-deoxyprostaglandin-F₂α.